CN114748503A - Method for storing whole blood and composition thereof - Google Patents
Method for storing whole blood and composition thereof Download PDFInfo
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- CN114748503A CN114748503A CN202210495860.1A CN202210495860A CN114748503A CN 114748503 A CN114748503 A CN 114748503A CN 202210495860 A CN202210495860 A CN 202210495860A CN 114748503 A CN114748503 A CN 114748503A
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- oxygen
- lrwb
- reduced
- plt
- whole blood
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- A61K35/14—Blood; Artificial blood
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- A—HUMAN NECESSITIES
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- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/02—Blood transfusion apparatus
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Abstract
The present application relates to methods of storing whole blood and compositions thereof. Methods and compositions for improving clinical outcomes in trauma patients receiving blood transfusions. Methods and compositions for improving the clinical outcome of blood transfusions in cancer patients are also provided.
Description
The present application is a divisional application of the Chinese patent application entitled "method for storing whole blood and composition thereof" filed as 18/5/2016, and filed as 201680036477.2, the original application was a Chinese national phase application of International application PCT/US 2016/033151.
Technical Field
The present disclosure relates to methods for improving the quality of whole blood available for infusion into a patient. Anaerobic storage of whole blood provides reduced cytokine levels and increased levels of 2, 3-diphosphoglycerate (2, 3-DPG) and Adenosine Triphosphate (ATP). The improved blood compositions are useful for infusing cancer and trauma patients.
Background
When stored in a conventional manner, stored blood undergoes a stability penalty associated with various storage impairments, including hemolysis, hemoglobin degradation, and reduced ATP and 2, 3-DPG concentrations. The effect of stability deterioration, for example during storage, when transfused into a patient manifests as a reduction in 24-hour in vivo recovery. Because of these and other medical sequelae of storing blood, various methods have been developed to minimize the impact of storage on blood and improve medical outcomes. See, for example, Zimring et al, "essential and cosmetic factors to a conditioner in an assisting the red cell storage division," in Blood, 125: 2185-90(2015).
Various methods have been developed to minimize storage damage and improve transfusion outcomes. One approach is to develop additive solutions during storage. Examples of such methods include: U.S. patent No.4,769,318 to Hamasaki et al and U.S. patent No.4,880,786 to Sasakawa et al are directed to additive solutions for blood preservation and activation. For example, in the case of a liquid,
(obtained from Citra Lab LLC, Braintree, MA) was added to the blood immediately before transfusion or after refrigeration (i.e.with glycerol at-80 ℃) to prolong storage time. U.S. Pat. No.6,447,987 to Hess et al relates to an additive solution for the cryopreservation of human erythrocytes. Another approach is to freeze the blood and prevent the development of storage lesions. Storage of frozen blood is known in the art, but such frozen blood has limitations. U.S. patent No.6,413,713 to serebrenikov relates to a method of storing blood at temperatures below 0 ℃. See Chaplin et al, "Blood Cells for transfer"Blood, 59: 1118-20(1982), and Valeri et al, "The summary, function, and physiology of human RBCs stored at 4 graded C in additive solution (AS-1, AS-3, or AS-5) for 42days and The n biochemical modified, freezen, thawed, washed, and stored at 4 graded C in solution chloride and glucose solution for 24 hours," Transfusion, 40: 1341-5(2000). Another approach involves a container for blood storage as provided by U.S. patent No.4,837,047 to Sato et al.
One method that has proven successful in improving blood quality and extending its utility is through the consumption of oxygen and storage under anaerobic conditions. Bitensky et al, U.S. Pat. No.5,624,794, Bitensky et al, U.S. Pat. No.6,162,396, and Bitensky, U.S. Pat. No.5,476,764 are directed to storage of red blood cells under hypoxic conditions. U.S. patent No.5,789,151 to Bitensky et al is directed to a blood storage additive solution. The benefits of storing blood under hypoxic conditions include increased levels of ATP and 2, 3-DPG, and reduced hemolysis. Storage of blood under hypoxic conditions can also result in reduced particulate levels, reduced deformability losses, reduced lipid and protein oxidation, and higher post-transfusion survival rates than blood stored under conventional conditions.
U.S. patent No.6,162,396 to Bitensky et al (the' 396 patent) discloses an anaerobic storage bag for blood storage that includes an oxygen impermeable outer layer, an oxygen permeable Red Blood Cell (RBC) compatible inner layer with an oxygen scrubber disposed between the inner and outer layers.
Although the effect of oxygen depletion on packed red blood cells has been explored, the effect of hypoxia on whole blood has not been reported. This is due in part to the lack of research on deoxygenation of whole blood, probably due to the expected deleterious effects of platelets being deprived of oxygen. More specifically, in view of the important role of platelets in the clotting process, there is concern that a decrease in platelet function may lead to coagulopathy and adverse consequences on clinical outcome.
The storage of platelets has been extensively studied to determine the most favorable conditions, including temperature, pH, O2And CO2And (4) concentration. The result of this work isPlatelets, which persist in the recipient after transfusion, require oxygen and room temperature storage. Murphy and Gardner indicated in 1975 that unwanted morphological changes were associated with reduced oxygen consumption. See Murphy et al, "plantlet storage at 22degrees C: role of gas transport plastics associates in maintence of vitality, "Blood 46 (2)": 209-218(1975). The authors observed that increasing the uptake of oxygen allowed aerobic metabolism (oxidative phosphorylation), resulting in a decrease in lactate production. At low PO2At levels, the increased lactic acid production is consistent with the pasteur effect. Moroff et al noted that continuous oxygen consumption was required to maintain the pH of stored platelets at 7. See "fans inducing Changes in pH reducing Storage of plate concentrators at 20-24 ℃ in Moroff et al," Vox Sanguinis 42 (1): 33-45(1982). The specially tailored container system is permeable to carbon dioxide and oxygen, preventing a fatal drop in pH. Such as Kakai ya et al, "Platlet preservation in large contacts," Vox Sanguinis 46 (2): 111-118(1984) it is known that the reason for maintaining platelet quality is the increased surface area available for gas exchange due to improved gas exchange conditions. The importance of maintaining oxygen levels during platelet storage has led to the development of gas permeable containers and the storage of platelets in oxygen-enriched air. See U.S. patent No.4,455,299 issued to Grode on 6/19/1984. The importance of oxygen for the storage of platelet viability is enhanced because in an oxygen deficient environment the lactic acid content increases by a factor of 5-8. See Kilkson et al, "Platetreme biology of Platetet proportions at 22 degreees C.," Blood 64 (2): 406-14(1984). Wallvik et al, "Platlet centers Stored at 22 ℃ Need Oxygen The Significication of Plastics in Platlet Preservation," Vox Sanguinis 45 (4): 303-311(1983), discloses that the preservation of oxygen five days before storage is critical for the preservation of platelets. Wallvik and colleagues also show that the maximum number of platelets that can be successfully stored for five days can be predicted based on the measurement of the oxygen diffusion capacity of the storage bag. See Wallvik et al, "The platform storage capacity of differential platform associates," Vox Sanguinis 58(1) : 40-4(1990). By providing a blood bag with sufficient gas exchange properties, the pH is maintained, preventing loss of ATP and release of alpha granular platelet factor 4(PF 4). Each of the above references is hereby incorporated in its entirety.
These findings lead to a standardization of practice, ensuring oxygenation of platelets during storage at room temperature to maximize post-transfusion viability. When platelets are stored at refrigerated temperatures, viability is lost after transfusion, making such platelets unsuitable for prophylactic transfusion to tumor patients who cannot produce platelets on their own. On the other hand, platelets stored at refrigerated temperatures maintain hemostatic function during transfusion. Thus, when platelets are administered to patients with traumatic bleeding, viability is less important than hemostatic activity. We demonstrate that refrigerated anaerobic storage of whole blood for 3 weeks produces hemostatic activity consistent with that of refrigerated traditionally stored whole blood, clearly indicating that the hemostatic activity of platelets remains cryogenically stored even in the absence of oxygen.
Although the consumption of oxygen in whole blood has been mentioned in the literature, the effect of anaerobic storage of whole blood has not been disclosed. As mentioned above, long-term survival (over 24 hours) of Platelets (PLTs) requires room temperature storage as well as oxygen during storage, which is well established. However, for hemorrhagic wound resuscitation, the long-term survival of PLTs is not important compared to their hemostatic potential. Recently, it has become apparent that patients transfused with stored or fresh whole blood as well as reconstituted whole blood (a mixture of plasma, red blood cells and platelets) have significantly reduced post-traumatic mortality. We have recently found that cryopreservation allows PLTs to be stored anaerobically and provides the known advantages of anaerobic storage of red blood cells observed in packed red blood cells in whole blood. More specifically, deoxygenated whole blood provides improved levels of 2, 3, -DPG, although coagulation is unexpectedly retained without introducing negative effects. The deformability of the red blood cells is maintained under deoxygenated conditions during storage.
Oxidative damage during storage has been considered to be a major contributor to packed red blood cell (pRBC) membrane damage, as suggested by the accumulation of lipid peroxidation markers such as isoprostane. Increased cytokine amounts during storage may also play a role in the development of storage lesions, with potential clinical implications for negative transfusion outcomes.
Certain patient populations are more susceptible to storage damage than others. Among these more sensitive populations, by way of non-limiting example, are trauma patients and cancer patients. Associated with the poor clinical outcome is the accumulation of Biological Response Modifiers (BRMs), which include cytokines that mediate inflammation, regulate cell growth, regulate angiogenesis, and regulate T helper cell function. Among these BRMs are interleukin 17(IL-17), eotaxin (CCL11), basic FGF (bFGF), macrophage inflammatory protein 1a (MIP-1a), monocyte chemotactic protein 1(MCP-1), platelet-derived growth factor (PDGF), tumor necrosis factor alpha (TNF-alpha), and Vascular Endothelial Growth Factor (VEGF). See Behrens et al, "Accumulation of biological response modifiers reducing red blood cell cold storage," Transfusion 49(Supp 13): 10A (2009). Cytokine accumulation during blood storage is also observed, and may be associated with adverse outcomes when administered perioperatively to cancer patients. See Benson et al "Accumulation of Pro-Cancer Cytokines in the Plasma Fraction of Stored Packed Red Cells," J gastroenterest Surg.16: 460-468(2012). Methods requiring blood storage result in reduced levels of BRM and cytokines, thereby improving patient outcomes.
Traumatic injury accounts for 30% of the life-year loss in the united states, far exceeding that of cancer (16% of life) and heart disease (12%). Trauma is a leading cause of death in patients between 1 and 46 years of age. Although bleeding death often occurs within 24 hours of traumatic injury, early death due to massive bleeding (within 3-6 hours) is preventable and can be quickly and properly attended to.
The injury control resuscitation (DCR) protocol describes the concept of using blood component balance ratios. DCR is rapidly becoming the standard for stopping bleeding and torsional shock in patients with acute bleeding wounds. In the civilian setting, the current blood banking business does not include a whole blood inventory, and therefore DCR employs serial blood transfusions to separate components (RBC, plasma, and platelets) so that the blood is "reconstituted" in the recipient. Earlier in the year, a large-scale Randomized Controlled Trial (RCT), using a randomized optimization of platelet to plasma ratio (PROPPR), compared the efficacy of "reconstituted blood" transfused at a 1: 1 unit ratio (plasma, platelets and red blood cells) with trauma patients at a 1: 2 ratio. In major trauma centers, a number of blood transfusion kits incorporate prepackaged blood products of Fresh Frozen Plasma (FFP), platelets and RBCs thawed at a ratio of 1: 1, and are now readily available.
Recent studies have shown that whole blood may be superior in treating patients with severe bleeding to control bleeding and reverse shock in life-threatening bleeding patients. The 2015 conference of the international conference on medicine for NHLBI transfusion medicine gave priority to the study of patients with severe bleeding from whole blood. Also, the THOR network of the International organization, which is devoted to injury-controlled resuscitation, has compared the efficacy and safety of whole blood with the hemorrhagic shock component. Because modern blood banks have no regular supply of whole blood, more than 80% of the trauma centers under investigation attempt to mimic the hemostatic, shock-reversing properties required for large-scale transfusion regimes with plasma, platelet and red blood cell ratios of 1: 1 to 1: 2 for traumatic and non-traumatic life-threatening bleeding cases. It is logically difficult to provide all three blood components quickly and safely, especially considering the need to thaw plasma in a center where a list of thawed plasma is not immediately available. Recent data also show that whole blood maintains platelet function and global hemostatic efficacy for up to 14 days at 4 ℃ better than 22 ℃.
In addition to the need for blood banks to provide whole blood for certain patient populations, the ability to conserve valuable blood resources is also important. In particular, blood banks typically discard whole blood inventory after 2 weeks (even if FDA regulations allow for longer service life) and therefore do not utilize valuable and often scarce resources. This ability to maximize blood resource value is particularly useful for small hospitals that act as class III and IV trauma centers, where an anoxic hemostatic whole blood product can be maintained under anaerobic conditions, followed by packed red blood cell processing. The present specification provides improved whole blood quality for trauma patients and further provides another packaged source of red blood cells with improved properties and reduced storage damage. The present description overcomes concerns regarding the consumption of valuable type-O negative RBCS (commonly used for whole blood infusion). Thus, anaerobic red blood cells can be obtained from oxygen-reduced whole blood and recycled to the hypoxic red blood cell unit, suitable for storage for up to six weeks. As provided herein, deoxygenated packed red blood cells can be obtained from unused oxygen-depleted whole blood for transfusion, or stored for later use under anaerobic conditions.
Disclosure of Invention
The present disclosure provides and includes methods for improving survival of a patient in need of multiple transfusions comprising providing stored red blood cells that have been oxygen reduced to a patient in need thereof undergoing a medical procedure.
The present disclosure provides and includes methods for improving survival of a cancer patient in need thereof following a perioperative blood transfusion, the methods comprising providing oxygen-reduced stored red blood cells to a cancer patient in need of undergoing a surgical procedure.
The present disclosure provides and includes methods for reducing a pro-cancer cytokine in stored blood, including depleting oxygen from the blood prior to storage, the methods including collecting blood in an anticoagulant solution, reducing leukocytes from the collected blood, and reducing oxygen Saturation (SO) prior to storage2) To below 30%, reducing the partial pressure of carbon dioxide before storage to below 60mmHg, and storing the oxygen and carbon dioxide reduced blood under anaerobic conditions.
The present disclosure provides and includes a blood composition for infusion into a wound patient in need thereof comprising deoxygenated leukoreduced whole blood in an anticoagulant solution and having a pre-existing oxygen Saturation (SO) of 20% or less 2) And a pre-stored partial pressure of carbon dioxide of less than 60mmHg, wherein the deoxygenated leukopenia whole blood has a level of 2, 3-DPG at 15 days that is higher than the initial 2, 3-DPG level of the deoxygenated leukopenia blood.
The present disclosure provides and includes methods of reducing inflammatory responses in a patient receiving a blood transfusion, the methods comprising delivering an oxygen-depleted blood product to a patient in need thereof, wherein the whole blood that is hypoxic has reduced levels of inflammatory cytokines after storage under anaerobic conditions.
The present disclosure provides and includes methods of reducing an immune response in a patient receiving a blood transfusion, the methods comprising delivering an oxygen-depleted blood product to a patient in need thereof, wherein the oxygen-depleted blood product has a reduced cytokine level after storage under anaerobic conditions. In aspects according to the disclosure, the immune response is immunomodulation or immunosuppression. In other aspects, the immune response is activation, including, for example, inflammation.
The present disclosure provides and includes methods for improving perfusion of oxygen in a patient in need thereof, the methods comprising delivering an oxygen-depleted blood product to the patient in need thereof, wherein the oxygen-depleted blood product has a higher RBC deformability than conventionally stored blood products.
The present disclosure provides and includes a method for managing a blood bank, comprising: maintaining a blood unit comprising oxygen-reduced whole blood and an anticoagulant or oxygen-reduced leukopenia whole blood and an anticoagulant; providing one or more units of blood in inventory for treating a patient; and recovering the blood units from the inventory to produce component-separated deoxygenated blood units. The present disclosure further provides for the use of the recycled blood unit for the preparation of a treatment of a regenerative blood unit for a trauma patient requiring massive transfusion.
The present disclosure provides and includes methods of providing a supply of blood products for transfusion medication comprising consuming oxygen or oxygen and carbon dioxide from whole blood to produce oxygen or oxygen and carbon dioxide reduced whole blood; and storing the oxygen or oxygen and carbon dioxide reduced whole blood for a period of time and providing the stored blood to a patient in need thereof; or storing the oxygen or oxygen and carbon dioxide reduced whole blood for a period of time and preparing oxygen or oxygen and carbon dioxide reduced packed red blood cells.
Drawings
The disclosure is disclosed with reference to the accompanying drawings, wherein:
FIGS. 1A to 1D are graphs showing cytokine measurements showing the reduced levels of eotaxin (1A) and RANTES (1B) in packaged red blood cells stored anaerobically. Fig. 1C shows reduced cell-free hemoglobin levels compared to packed red blood cells with aerobic storage. FIG. 1D shows the reduced isoprostane content in packaged red blood cells stored anaerobically. Dashed line ═ blood stored aerobically; solid line refers to anaerobically stored blood.
Fig. 2A to 2G are graphs showing the results of two experiments according to the present invention comparing the oxygen reduction, oxygen and carbon dioxide reduction and the storage amount of leukocyte-reduced whole blood in anticoagulant solution CPD (LRWB/CPD) collected within 21 days of conventional storage of LRWB/CPD. FIG. 2A shows 2, 3-DPG levels. FIG. 2B shows ATP levels. Fig. 2C shows pH. Fig. 2D shows the platelet count. Fig. 2E presents potassium levels. FIG. 2F presents the 2, 3-DPG levels (T) of FIG. 2A relative to day 00) The data is redrawn. FIG. 2G shows the data of FIG. 2B relative to day 0 ATP levels (T)0) And (4) re-drawing the graph. The key is as follows: sample c68/80 was conventionally stored blood with an initial oxygen saturation of 68% and a partial pressure of carbon dioxide of 80 mmHg; sample c50/94 is conventionally stored blood with an initial oxygen saturation of 50% and CO of 94mmHg2Partial pressure; sample sc91/75 was conventionally stored blood with an initial oxygen saturation of 91% and CO of 75mmHg2Partial pressure; sample sc69/87 was conventionally stored blood with an initial oxygen saturation of 69% and CO of 87mmHg2Partial pressure; sample tc5/78 was oxygen-depleted, anaerobically stored blood with 5% initial oxygen saturation and 78mmHg CO2Partial pressure; sample tc7/64 was oxygen-depleted, anaerobically stored blood with 7% initial oxygen saturation and 64mmHg CO 2Partial pressure; sample T5/28 is oxygen and carbon dioxide depleted, anaerobically stored blood with 5% initial oxygen saturation and 28mmHg CO2Partial pressure; sample T4/26 is oxygen and carbon dioxide depleted, anaerobically stored blood with 4% initial oxygen saturation and 26mmHg CO2And (4) partial pressure.
FIGS. 3A-3D are graphs showing the results of two experiments comparing anticoagulant solution CPDA1(LRWB/CPDA1) at oxygen reduction,Oxygen and carbon dioxide reduction and leukoreduced whole blood collected within 21 days of conventional storage of LRWB/CPDA 1. FIG. 3A shows 2, 3-DPG levels. FIG. 3B shows ATP levels. FIG. 3C shows 2, 3-DPG levels (T) relative to day 00) The data of fig. 3A is redrawn. FIG. 3D presents ATP levels (T) versus day 00) The data of fig. 3B is redrawn. The key is as follows: sample c32/98 was conventionally stored blood with an initial oxygen saturation of 32% and a partial carbon dioxide pressure of 98 mmHg; sample c56/86 was conventionally stored blood with an initial oxygen saturation of 56% and CO of 86mmHg2Partial pressure; sample sc59/95 is conventionally stored blood with an initial oxygen saturation of 59% and CO of 95mmHg2Partial pressure; sample sc82/84 was conventionally stored blood with an initial oxygen saturation of 82% and CO of 84mmHg 2Partial pressure; sample tc7/80 was oxygen depleted, anaerobically stored blood with 7% initial oxygen saturation and 80mmHg CO2Partial pressure; sample tc6/77 is oxygen depleted, anaerobically stored blood with 6% initial oxygen saturation and 77mmHg CO2Partial pressure; sample T5/28 is oxygen and carbon dioxide depleted, anaerobically stored blood with 5% initial oxygen saturation and 28mmHg CO2Partial pressure; sample T7/23 is oxygen and carbon dioxide depleted, anaerobically stored blood with 7% initial oxygen saturation and 23mmHg CO2And (4) partial pressure.
Fig. 4A to 4C are graphs showing experimental results according to the present disclosure comparing leukocyte-reduced whole blood collected in anticoagulant solution CPDA1(LRWB/CPDA1) collected in oxygen-reduced (OR), oxygen and carbon dioxide-reduced (OCR) and traditionally stored LRWB/CPDA1 over a period of 21 days. FIG. 4A shows ATP levels in OR-LRWB/CPDA1, OCR-LRWB/CPDA1 and conventionally stored LRWB/CPDA 1. FIG. 4B shows the levels of 2, 3-DPG in OR-LRWB/CPDA1, OCR-LRWB/CPDA1, and traditionally stored LRWB/CPDA 1. FIG. 4C shows the percent hemolysis in OR-LRWB/CPDA1, OCR-LRWB/CPDA1 and conventionally stored LRWB/CPDA 1. In the graphs presented in fig. 4A to 4C, the small dashed line OR-LRWB/CPDA1 stores blood, the dashed line ORC-LRWB/CPDA1 stores blood, and the solid line conventional stored blood.
Fig. 5A to 5D are graphs showing the results of experiments according to the present invention comparing the storage amount of leukocyte-reduced whole blood in the anticoagulant solution CPDA1(LRWB/CPDA1) collected within 21 days for oxygen and carbon dioxide reduced and for the conventionally stored LRWB/CPDA 1. FIG. 5A shows the partial thrombin time (sec) (aPTT) activated in OCR-LRWB/CPDA1 and the traditionally stored LRWB/CPDA 1. FIG. 5B shows prothrombin time (sec) (PT) in OCR-LRWB/CPDA1 and in conventional stock LRWB/CPDA 1. FIG. 5C shows fibrinogen levels in OCR-LRWB/CPDA1 and in traditionally stored LRWB/CPDA 1. FIG. 5D shows the level of D-dimer in OCR-LRWB/CPDA1 and in traditionally stored LRWB/CPDA 1. In the graph showing the plasma coagulation parameters, the dashed line ORC-LRWB/CPDA1 stores blood and the solid line conventional stored blood.
Fig. 6A to 6E are graphs showing the results of experiments according to the present invention comparing the storage of leukocyte-reduced whole blood in the anticoagulant solution CPDA1(LRWB/CPDA1) collected over 21 days with oxygen and carbon dioxide reduced and the conventional stored LRWB/CPDA 1. FIG. 6A shows the levels of factor V in OCR-LRWB/CPDA1 and in the conventionally stored LRWB/CPDA 1. FIG. 6B shows the levels of factor VIII in OCR-LRWB/CPDA1 and in traditionally stored LRWB/CPDA 1. FIG. 6C shows protein C activity in OCR-LRWB/CPDA1 and traditionally stored LRWB/CPDA 1. FIG. 6D presents protein S activity in OCR-LRWB/CPDA1 and traditionally stored LRWB/CPDA 1. FIG. 6E shows the levels of von Willebrand factor (vWF) in OCR-LRWB/CPDA1 and in traditionally stored LRWB/CPDA 1. In the graph showing plasma coagulation factors, the dotted line ORC-LRWB/CPDA1 stores blood and the solid line conventional stored blood.
Fig. 7A to 7D are graphs showing experimental results according to the present invention comparing the leukocyte-reduced whole blood volume in anticoagulant solution CPDA1(LRWB/CPDA1) collected within 21 days of oxygen and carbon dioxide-reduced (OCR) and conventional stored LRWB/CPDA 1. FIG. 7A shows the speed at which fibrin aggregation and cross-linking occurs (TEG angle) in OCR-LRWB/CPDA1 and conventional stock LRWB/CPDA 1. FIG. 7B shows a comparison of hemodynamics (TEG K) in OCR-LRWB/CPDA1 and the traditionally stored LRWB/CPDA 1. FIG. 7C shows the maximum amplitude in OCR-LRWB/CPDA1 and the conventionally stored LRWB/CPDA 1. FIG. 7D shows the reaction times of OCR-LRWB/CPDA1 and conventional stock LRWB/CPDA 1. In the graph presenting the Thromboelastography (TEG) parameters, the dashed line ORC-LRWB/CPDA1 stores blood and the solid line conventional stored blood.
Detailed Description
Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. One skilled in the art will recognize that many methods may be used in the practice of the present disclosure. Indeed, the disclosure is in no way limited to the methods and materials described. Any references cited herein are incorporated by reference in their entirety. For the purposes of this disclosure, the following terms are defined below.
As used herein, the term "patient" includes a person in need of a medical procedure to receive a blood product.
As used herein, the term "multiple transfusions" includes patients who receive more than 195 units of blood. In another aspect, multiple transfusions may comprise receiving at least 1 × 10 transfusions5Blood mL in patients. In another aspect, multiple transfusions comprise receiving 1 to 1X 105Blood mL in patients. In another aspect, multiple transfusions comprise receiving 1 × 10 transfusions4To 1 × 105Blood mL in patients.
As used herein, the term "blood" refers to whole blood, leuko-reduced RBCs, platelet-reduced RBCs, and both leuko-and platelet-reduced RBCs. The term blood also includes packed red blood cells, thrombocytopenic packed red blood cells, leukopenia packed red blood cells (LRpRBC) and white blood cells and thrombocytopenic packed red blood cells. The temperature of the blood may start at the normothermic temperature of 37 ℃ at the time of collection, and once the blood leaves the patient's body, it drops immediately to about 30 ℃, then after about 6 hours, it drops further to room temperature, and finally is refrigerated between about 4 ℃ and 6 ℃, depending on the stage of the collection process.
As used herein, "blood product" includes isolated platelets, plasma, or white blood cells.
As used herein, "recovered blood product" includes isolated platelets, plasma, or white blood cells collected from a donor.
As used herein, "salvaged blood" includes whole blood and red blood cells collected from a donor and pre-stored under reduced oxygen conditions. In one aspect of the disclosure, suitable blood for use in the method comprises oxygen-reduced leukopenia packaged red blood cells (OR-LRpRBC), oxygen-reduced leukopenia packaged red blood cells comprising platelets (OR-LRpRBC + PLT), oxygen and carbon dioxide-reduced leukopenia packaged red blood cells (OCR-LRpRBC) OR oxygen and carbon dioxide-reduced leukopenia packaged red blood cells comprising platelets obtained from oxygen-reduced leukopenia whole blood (OR-LRWB) (OCR-LRpRBC + PLT), whole blood with oxygen-reduced leukopenia and containing platelets (OR-LRWB + PLT), whole blood with oxygen-and carbon-dioxide-reduced leukopenia (OCR-LRWB), whole blood with oxygen-and carbon-dioxide-reduced leukopenia and containing platelets stored for at least one week (OCR-LRWB + PLT). On the other hand, suitable blood storage for this method is up to 42 days. On the other hand, suitable blood storage for this method is up to 56 days. On the other hand, suitable blood for this method is stored for up to 64 days.
As used herein, a method of obtaining a "component-separated blood product" includes obtaining recirculated blood from a blood bank inventory and separating into platelets, plasma, and leukocytes. Suitable blood for use in the method comprises oxygen with an anticoagulant and oxygen-reduced leukoreduced whole blood with an anticoagulant. In one aspect of the present disclosure, the oxygen-reduced blood separated components are stored for up to six weeks. In another aspect, separating the components of the oxygen-reduced blood includes an additive solution. In certain aspects, the additive solution may be AS-1. In certain aspects, the additive solution is AS-3 (R)
). In certain aspects, the additive solution is AS-5. In certain aspects, the additive solution is SAGM. In certain aspects, the additive solution is PAGG-SM. In certain aspects, the additive solution is PAGG-GM. In certain aspects, the additive solution is MAP. In certain aspects, the additive solution is SOLX. In certain aspects, the additive solution is an ESOL. In some aspects, addingThe agent solution is EAS 61. In certain aspects, the additive solution is OFAS 1. In certain aspects, the additive solution is OFAS 3. In certain aspects, the additive solution is AS-1, AS-3 (C)
) AS-5, SAGM, PAGG-SM, PAGG-GM, MAP, SOLX, ESOL, EAS61, OFAS1, and OFAS3, alone or in combination.
As used herein, "reconstituted WB" includes providing platelets, RBCs, and plasma in parallel with the patient during transfusion.
As used herein, "derivatized WB" includes whole blood with reduced oxygen as well as reduced oxygen and carbon dioxide.
As used herein, "stored red blood cells" includes oxygen reduced or oxygen and carbon dioxide reduced red blood cells stored at 1 to 6 ℃. In one aspect, the stored red blood cells comprise Red Blood Cells (RBCs) present in whole blood. In another aspect, the stored red blood cells include red blood cells present in leukoreduced whole blood. In another aspect, the stored red blood cells include Red Blood Cells (RBCs) present in leukoreduced RBCs. In another aspect, the stored red blood cells include Red Blood Cells (RBCs) present in thrombocytopenic RBCs. In another aspect, the stored red blood cells include Red Blood Cells (RBCs) present in both leukoreduced and thrombocytopenic red blood cells.
As used herein, "whole blood" includes White Blood Cells (WBCs), platelets suspended in plasma, and also includes electrolytes, hormones, vitamins, antibodies, and the like. In whole blood, leukocytes are usually between 4.5 and 11.0X 109Between individual cells/L, normal RBC levels ranged from 4.6-6.2X 10 for males 12L, female is 4.2-5.4 × 1012L is the ratio of the total weight of the composition to the total weight of the composition. Normal hematocrit or percent packed cell volumes are about 40-54% for men and about 38-47% for women. The platelet count for men and women is typically 150-450X 109L is the ratio of the total weight of the composition to the total weight of the composition. Whole blood is collected from a donor and is typically used in combination with an anticoagulant. Whole blood was initially collected at about 37 ℃ and cooled rapidly to about 30 ℃ during and shortly after collection, but slowly cooled to ambient temperature over about 6 hours. Whole blood can be started at the time of collection, at 30-37 ℃, or at room temperature (typically about 25 ℃) according to the methods of the present disclosure. As used herein, a "unit" of blood is about 450-500ml, including the anticoagulant. Suitable anticoagulants include CPD, CPDA1, ACD and ACD-A. As used herein, "time to collect" (Tc) is the time at which blood is collected from a patient.
As used herein, "red blood cells" (RBCs), stored red blood cells, oxygen-reduced red blood cells, oxygen-and carbon dioxide-reduced red blood cells, include red blood cells, leukopenia RBCs, thrombocytopenia RBCs, white blood cells, thrombocytopenia RBCs, packed red blood cells (pRBC) in whole blood. Erythrocytes are in a dynamic state in humans. Red blood cells contain hemoglobin, an iron-containing protein that carries oxygen throughout the body, causing the blood to become red. The percentage of blood volume consisting of red blood cells is called hematocrit. As used herein, unless otherwise defined, RBCs also include packed red blood cells (pRBC). Packed red blood cells are prepared from whole blood using centrifugation techniques well known in the art. As used herein, unless otherwise indicated, the hematocrit of pRBC is about 70%. As used herein, oxygen reduced RBCs (OR-RBCs) can include oxygen and carbon dioxide (OCR-) reduced RBCs (OCR-RBCs).
As used herein, "leukoreduced whole blood" (LRWB) includes whole blood that is an anticoagulant that is typically processed by filtration or centrifugation to remove white blood cells and platelets. Leukoreduced whole blood has at least 5 log reduction in leukocyte levels.
As used herein, "oxygen reduced leukopenia whole blood" (OR-LRWB) may include oxygen and carbon dioxide reduced leukopenia whole blood (OCR-LRWB).
As used herein, "leukoreduced and platelet-containing whole blood" (LRWB + PLT) includes oxygen reduced (OR-) whole blood with an anticoagulant and platelet-conservative filters with leukopenia. As used herein, whole blood with reduced leukocytes and containing platelets by oxygen (OR-LRWB + PLT) may include whole blood with reduced leukocytes by oxygen and carbon dioxide (OCR-LRWB + PLT) and containing platelets.
As used herein, "leukopenia packaged red blood cells" (LRpRBC) includes packaged red blood cells with oxygen reduced (OR-) whole blood having an anticoagulant that is filtered OR centrifuged to remove white blood cells. As used herein, oxygen-reduced leukopenia packaged red blood cells (OR-LRpRBC) may include oxygen and carbon dioxide-reduced leukopenia packaged red blood cells (OCR-LRpRBC).
As used herein, "packed red blood cells that are leukopenic and contain platelets" (LRpRBC + PLT) includes packed red blood cells with platelets obtained from oxygen-reduced whole blood with an anticoagulant that removes white blood cells through a platelet protection filter. As used herein, oxygen-reduced leukopenia and platelet containing packaged red blood cells (OR-LRpRBC + PLT) may include oxygen and carbon dioxide-reduced leukopenia and platelet containing packaged red blood cells (OCR-LRpRBC + PLT).
In aspects of the present disclosure, the methods and compositions may include adding an additive solution to the packaged RBCs to form a suspension. Many additive solutions are known in the art. In certain aspects, the additive solution may be selected from the group consisting of AS-1, AS-3 (R) ((R))
) AS-5, SAGM, PAGG-SM, PAGG-GM, MAP, AS-7, ESOL-5, EAS61, OFAS1, and OFAS3, alone or in combination. In "Use of adaptive preservation solution for managed storage of low vision AS-1 red blood cells," Br J Haema tol., 57(3) "by Heaton et al: 467-78(1984) disclose the additive AS-1. In another aspect, the additive solution can have a pH of 5.0 to 9.0. In another aspect, the additive may include an antioxidant. In some aspects according to the present disclosure, the antioxidant may be an enzyme inhibitor of quercetin, alpha-tocopherol, ascorbic acid, or oxidase.
As used herein, the term "about" refers to ± 10%.
The terms "comprising," including, "" containing, "" having, "and conjugates thereof mean" including, but not limited to.
The term "consisting of means" including and limited to ".
The term "consisting essentially of" means that the composition, method, or structure may include additional ingredients, steps, and/or portions, but only if the additional ingredients, steps, and/or portions do not materially alter the basic and novel characteristics of the claimed composition, method, or structure.
As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. For example, the term "a compound" or "at least one compound" may include a plurality of compounds, including mixtures thereof.
Throughout this application, various aspects of the disclosure may be presented in a range format. It is to be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range. For example, a description of a range of "1 to 6," etc. should be considered to have particular disclosed sub-ranges, such as "1 to 3," "1 to 4," "1 to 5," "2 to 4," "2 to 6," "3 to 6," etc., as well as individual numbers within that range, such as 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.
Whenever a numerical range is indicated herein, it is intended to include any referenced number (fractional or integer) within the indicated range. "range/range" and "range/range" from "first indicating number" to "second indicating number" between the first indicating number and the second indicating number are used interchangeably herein and are intended to include the first and second indicating numbers and all fractional and integer numbers therebetween.
As used herein, the term "method" refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by those skilled in the chemical, pharmacological, biological, biochemical and medical arts.
As used herein, the term "equivalent" refers to a measurement of oxygen reduced leukopenia whole blood (OR-LRWB), oxygen reduced leukopenia whole blood containing platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukopenia whole blood (OCR-LRWB), OR oxygen and carbon dioxide reduced leukopenia whole blood containing platelets (OCR-LRWB + PLT), the sample size being at least 5 within 1 standard deviation of each other at each compared measurement condition when comparing measurements of otherwise equivalently processed conventionally stored blood.
As used herein, the term "greater" OR "increase" refers to a measurement of oxygen reduced leukopenia whole blood (OR-LRWB), oxygen reduced leukopenia whole blood containing platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukopenia whole blood (OCR-LRWB), OR oxygen and carbon dioxide reduced leukopenia whole blood containing platelets (OCR-LRWB + PLT), when comparing OR-WB, at least 1 standard deviation is greater than a measurement of otherwise equivalently processed conventionally stored blood, with a sample size of at least 5 for each of the compared measurement conditions.
The term "reduce" OR "reducing" as used herein means a measurement of oxygen reduced leukoreduced whole blood (OR-LRWB), oxygen reduced leukoreduced whole blood containing platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukoreduced whole blood (OCR-LRWB) OR oxygen and carbon dioxide reduced leukoreduced whole blood containing platelets (OCR-LRWB + PLT), when comparing OR-WB, at least 1 standard deviation is lower compared to a measurement of otherwise equivalently processed conventionally stored blood, the sample size per comparison measurement condition being at least 5.
As used herein, the terms "conventional storage", "conventional storage" and "conventional conditions" include: whole blood, leukopenia RBCs, thrombocytopenic RBCs, leukocytes, thrombocytopenic RBCs, packaged red blood cells, thrombocytopenic packaged red blood cells, leukopenia packaged red blood cells (LRpRBC), leukocytes, and thrombocytopenic packaged red blood cells stored in an oxygen and carbon dioxide permeable container without a gas reduction step at 1 to 6 ℃ prior to storage. In one aspect of the present disclosure, oxygen and carbon dioxide increase over time to ambient levels in conventionally stored whole blood, leukopenia RBCs, thrombocytopenic RBCs, leukopenia and thrombocytopenic RBCs, packed red blood cells, thrombocytopenic packed red blood cells, leukopenia packed red blood cells (LRpRBC), white blood cells, and thrombocytopenic packed red blood cells due to the permeability of the oxygen and carbon dioxide reservoirs. Although not conventionally considered conventional, for purposes of this disclosure, conventional storage may include storage at temperatures above 6 ℃. Moreover, while not traditionally considered conventional, for purposes of this disclosure, conventional storage may include storage at refrigerated temperatures.
The present disclosure provides and includes methods of providing desired characteristics of blood products for transfusion. It has been found that the depletion of oxygen from packed erythrocytes leads to a reduction in the accumulation of unbound cytokines, in particular RANTES (CC motif chemokine ligand 5, CCL5) and eotaxin (CC motif chemokine ligand 11, CCL11), as well as to a reduction in the accumulation of cell-free hemoglobin and 8-isoprostaglandin F2α. Without being limited by theory, it is believed that RANTES and eotaxin are typically sequestered by binding to DARC (atypical chemokine receptor 1, ACKR1), and oxidative stress damages DARC and releases the bound chemokine. Thus, although the total content of chemokines is unchanged, the effective concentration (e.g., freely diffusing and unbound) increases and can be used to affect the infused patient. As will be appreciated, the presence of these active chemokines (acting in a dose-dependent manner) may be harmful to wounds and other patients who have been subjected to two or more transfusions. In addition to the required efficient oxygen transport associated with elevated 2, 3-DPG values, these findings suggest an unexpected benefit of anaerobically stored blood and provide a potential reduction of some components of storage damage resulting from pRBC oxidative damage during storage. These cytokines are known to correlate with patient outcomes in some patient populations And (4) carrying out negative correlation. Thus, the discovery that unbound cytokine accumulation can be reduced provides an improved method of treating patients who are sensitive to cytokines.
The present disclosure provides and includes improving the survival of patients in need of multiple transfusions by providing stored red blood cells that have been subjected to oxygen depletion (OR-stored RBCs) to patients in need of receiving a medical procedure. Without being limited by theory, it is believed that an increase in cytokine levels has an adverse effect on recipient patients, increasing morbidity. In one aspect, the stored red blood cells are Oxygen Reduced (OR). On the other hand, stored red blood cells are both oxygen and carbon dioxide reduced (OCR). As shown in the examples, ATP levels decreased and were maintained at lower levels for at least 15 days in OCR samples, while ATP levels increased in OR samples compared to conventionally stored samples (see fig. 4A). As shown in the examples, in the OCR samples, the level of 2, 3-DPG was increased and maintained at the high level for at least 15 days, while in the OR samples, the level of 2, 3-DPG was increased from the conventional storage, but not higher than the level of 2, 3-DPG of the OCR samples (see fig. 4B). Furthermore, as shown in the examples, OR, OCR and hemolysis in the conventionally stored samples were comparable.
In one aspect of the disclosure, the cytokine includes monocyte chemoattractant protein-1 (MCP-1). In another aspect, cytokines include regulation of expression and secretion (RANTES) by activated normal T cells. In another aspect, the cytokine comprises angiogenin. In another aspect of the disclosure, the cytokine comprises tumor necrosis factor-alpha (TNF-a). In another aspect, the cytokine comprises Epidermal Growth Factor (EGF). In another aspect, the cytokine comprises Platelet Derived Growth Factor (PDGF).
In one aspect of the disclosure, the level of factor RANTES is less than 500pg/ml after 21 days under OR conditions. On the other hand, after 21 days under OR conditions, the level of factor RANTES is less than 400 pg/ml. On the other hand, after 21 days under OR conditions, the level of factor RANTES was less than 300 pg/ml. On the other hand, after 21 days under OR conditions, the level of factor RANTES is greater than 100 pg/ml. On the other hand, after 21 days under OR conditions, the level of factor RANTES was between 0 and 300 pg/ml.
In one aspect of the disclosure, the level of eotaxin is less than 150pg/ml after 21 days under OR conditions. On the other hand, after 21 days under OR conditions, eotaxin levels were less than 100 pg/ml. On the other hand, eotaxin levels were 0 to 100pg/ml after 21 days under OR conditions. On the other hand, after 21 days under OR conditions, the level of eotaxin is preferably 100 pg/ml. In another aspect, the level of eotaxin is greater than 100pg/ml after 21 days under OR conditions. On the other hand, eotaxin levels were 0-300pg/ml after 21 days under OR conditions.
In aspects according to the disclosure, the OR-stored RBCs are selected from: oxygen-reduced leukopenia whole blood (OR-LRWB), oxygen-reduced leukopenia whole blood comprising platelets (OR-LRWB + PLT), oxygen-reduced leukopenia packaged red blood cells (OR-LRpRBC), oxygen-reduced leukopenia packaged red blood cells comprising platelets (OR-LRpRBC + PLT), oxygen-and carbon dioxide-reduced leukopenia whole blood (OCR-LRWB), oxygen-and carbon dioxide-reduced leukopenia whole blood comprising platelets (OCR-LRWB + PLT), oxygen-and carbon dioxide-reduced leukopenia packaged red blood cells (OCR-LRpRBC), oxygen-and carbon dioxide-reduced leukopenia packaged red blood cells comprising platelets (OCR-LRpRBC + PLT), and combinations thereof. In other aspects, wherein the OR-stored RBCs comprise oxygen reduced leukoreduced whole blood (OR-LRWB), oxygen reduced leukoreduced whole blood comprising platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukoreduced whole blood (OCR-LRWB), oxygen and carbon dioxide reduced leukoreduced whole blood comprising platelets (OCR-LRWB + PLT).
In one aspect, the patient requiring multiple transfusions is a trauma patient. On the other hand, patients requiring multiple transfusions are transplant patients. On the other hand, patients requiring multiple transfusions are cardiac surgery patients. On the other hand, patients requiring multiple transfusions are obstetrical patients. On the other hand, patients requiring multiple transfusions are Gastrointestinal (GI) surgery patients. In another aspect, the patient is an orthopaedic patient.
In one aspect, the patient requiring multiple transfusions is a trauma patient. On the other hand, patients requiring multiple transfusions are hemorrhagic trauma patients. On the other hand, patients requiring multiple transfusions are blunt trauma patients.
In one aspect, reducing cytokines in oxygen-reduced stored red blood cells provides improved treatment for cancer patients in need of blood transfusion. It is known in the art that cytokines are inversely correlated with patient outcome of surgical treatment of cancer patients in patients receiving perioperative blood transfusions. In one aspect, the oxygen-depleted cytokine-depleted blood product is provided to a cancer patient prior to performing surgery. On the other hand, oxygen-poor, cytokine-reduced blood products are provided to cancer patients during surgery. In another aspect, an oxygen-deficient, cytokine-depleted blood product is provided to a cancer patient after surgery.
In aspects according to the present disclosure, oxygen reduced leukoreduced whole blood (OR-LRWB), oxygen reduced leukoreduced whole blood containing platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukoreduced whole blood (OCR-LRWB), oxygen and carbon dioxide reduced leukoreduced whole blood containing platelets (OCR-LRWB + PLT) have higher levels of 2, 3-DPG than conventionally stored leukoreduced Whole Blood (WB) and provide improved oxygen delivery. Under anaerobic conditions, 2, 3-DPG levels can be maintained in whole blood for up to 4 weeks. In one aspect, 2, 3-DPG levels are maintained above 50% of physiological levels for up to four weeks. In aspects according to the present disclosure, improved levels of 2, 3-DPG are maintained at 2 weeks. In other aspects, 2, 3-DPG levels are maintained for three weeks. In one aspect, the 2, 3-DPG level of oxygen reduced leukopenia whole blood (OR-LRWB), oxygen reduced leukopenia whole blood comprising platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukopenia whole blood (OCR-LRWB), oxygen and carbon dioxide reduced leukopenia whole blood comprising platelets (OCR-LRWB + PLT) is at least 80% OR greater than the 2, 3-DPG level of blood on day 0. In another aspect, the 2, 3-DPG level of oxygen reduced leukopenia whole blood (OR-LRWB), oxygen reduced leukopenia whole blood comprising platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukopenia whole blood (OCR-LRWB), oxygen and carbon dioxide reduced leukopenia whole blood comprising platelets (OCR-LRWB + PLT) is at least 5 to 20DPG μmol/gHb.
Also provided and included in the present disclosure are: oxygen-reduced leukoreduced whole blood (OR-LRWB), oxygen-reduced leukoreduced whole blood comprising platelets (OR-LRWB + PLT), oxygen-and carbon-dioxide-reduced leukoreduced whole blood (OCR-LRWB), oxygen-and carbon-dioxide-reduced leukoreduced whole blood comprising platelets (OCR-LRWB + PLT). Whole blood of platelets (OCR-LRWB + PLT) has been depleted from whole blood (OR-WB), with reduced levels of Biological Response Modifiers (BRMs) relative to conventionally stored whole blood. In certain aspects, the BRM present in the oxygen reduced leukopenia whole blood (OR-LRWB), the oxygen reduced leukopenia whole blood including platelets (OR-LRWB + PLT), the oxygen and carbon dioxide reduced leukopenia whole blood (OCR-LRWB), the oxygen and carbon dioxide reduced leukopenia whole blood including platelets (OCR-LRWB + PLT) is about half of the volume of conventionally stored blood after 21 days. In one aspect, the oxygen-reduced leukopenia whole blood (OR-LRWB), the oxygen-reduced leukopenia whole blood comprising platelets (OR-LRWB + PLT), the oxygen-and carbon dioxide-reduced leukopenia whole blood (OCR-LRWB), the oxygen-and carbon dioxide-reduced leukopenia whole blood comprising platelets (OCR-LRWB + PLT) have relatively unchanged cytokine levels after 10 days of storage under anaerobic conditions. On the other hand, cytokine levels were relatively unchanged after 30 days of storage. On the other hand, cytokine levels were relatively unchanged after 40 days of storage. As used herein, "relatively unchanged" means that the concentration of cytokine is normalized to hemoglobin level within 1 standard deviation of the initial normalized concentration of cytokine.
In certain aspects, oxygen reduced leukopenia whole blood (OR-LRWB), oxygen reduced leukopenia platelet containing whole blood (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukopenia whole blood (OCR-LRWB + PLT) has reduced cytokine levels of eosinophils as compared to conventionally stored whole blood. In certain aspects, the level of eotaxin in oxygen reduced leukoreduced whole blood (OR-LRWB), oxygen reduced leukoreduced whole blood containing platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukoreduced whole blood (OCR-LRWB), oxygen and carbon dioxide reduced leukoreduced whole blood containing platelets (OCR-LRWB + PLT) is about half of the level of eotaxin in conventionally stored blood after normalization of hemoglobin concentration over 21 days. In one aspect, the level of eotaxin in oxygen reduced leukoreduced whole blood (OR-LRWB), oxygen reduced leukoreduced whole blood containing platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukoreduced whole blood (OCR-LRWB), oxygen and carbon dioxide reduced leukoreduced whole blood containing platelets (OCR-LRWB + PLT) is about 25% OR less of the level of eotaxin present in conventionally stored blood after 40 days.
In certain aspects, oxygen reduced leukopenia whole blood (OR-LRWB), oxygen reduced leukopenia whole blood including platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukopenia whole blood (OCR-LRWB), oxygen and carbon dioxide reduced leukopenia whole blood including platelets (OCR-LRWB + PLT) has reduced levels of the cytokine RANTES (modulating activation, normal T cell expression and secretion) compared to conventionally stored whole blood. In one aspect, the level of RANTES in oxygen-reduced leukoreduced whole blood (OR-LRWB), oxygen-reduced leukoreduced whole blood containing platelets (OR-LRWB + PLT), oxygen-and carbon dioxide-reduced leukoreduced whole blood (OCR-LRWB), oxygen-and carbon dioxide-reduced leukoreduced whole blood containing platelets (OCR-LRWB + PLT) is about half the level of RANTES present in conventionally stored blood after normalization of hemoglobin concentration over 21 days. In one aspect, the level of RANTES in oxygen reduced leukoreduced whole blood (OR-LRWB), oxygen reduced leukoreduced whole blood containing platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukoreduced whole blood (OCR-LRWB), oxygen and carbon dioxide reduced leukoreduced whole blood containing platelets (OCR-LRWB + PLT) is about 25% OR less of the level of RANTES present in conventionally stored blood after 40 days.
In certain aspects, the oxygen reduced leukopenia whole blood (OR-LRWB), the oxygen reduced leukopenia whole blood comprising platelets (OR-LRWB + PLT), the oxygen and carbon dioxide reduced leukopenia whole blood (OCR-LRWB), the oxygen and carbon dioxide reduced leukopenia whole blood comprising platelets (OCR-LRWB + PLT) has reduced levels of monocyte chemoattractant protein-1 (MCP-1) as compared to conventionally stored whole blood. In one aspect, the level of MCP-1 in oxygen reduced leukoreduced whole blood (OR-LRWB), oxygen reduced leukoreduced whole blood containing platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukoreduced whole blood (OCR-LRWB), oxygen and carbon dioxide reduced leukoreduced whole blood containing platelets (OCR-LRWB + PLT) is about half of the level of MCP-1 present in conventionally stored blood after normalization of hemoglobin concentration for 21 days. In one aspect, the level of MCP-1 in the levelofMCP-lin oxygen reduced leukopenia whole blood (OR-LRWB), oxygen reduced leukopenia whole blood including platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukopenia whole blood (OCR-LRWB), oxygen and carbon dioxide reduced leukopenia whole blood including platelets (OCR-LRWB + PLT) is about 25% OR less of the level of MCP-1 present in conventionally stored blood after 40 days.
In certain aspects, the oxygen reduced leukoreduced whole blood (OR-LRWB), the oxygen reduced leukoreduced whole blood comprising platelets (OR-LRWB + PLT), the oxygen and carbon dioxide reduced leukoreduced whole blood (OCR-LRWB), the oxygen and carbon dioxide reduced leukoreduced whole blood comprising platelets (OCR-LRWB + PLT) have reduced levels of angiogenin as compared to conventionally stored whole blood. In one aspect, the level of angiogenin in oxygen reduced leukoreduced whole blood (OR-LRWB), oxygen reduced leukoreduced whole blood containing platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukoreduced whole blood (OCR-LRWB), oxygen and carbon dioxide reduced leukoreduced whole blood containing platelets (OCR-LRWB + PLT) is about half of the level of angiogenin present in conventionally stored blood following normalization of hemoglobin concentration over 21 days. In one aspect, the level of angiogenin in oxygen reduced leukoreduced whole blood (OR-LRWB), oxygen reduced leukoreduced whole blood comprising platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukoreduced whole blood (OCR-LRWB), oxygen and carbon dioxide reduced leukoreduced whole blood comprising platelets (OCR-LRWB + PLT) is about 25% OR less of the level of angiogenin present in conventionally stored blood after 40 days.
In certain aspects, the oxygen reduced leukopenia whole blood (OR-LRWB), the oxygen reduced leukopenia whole blood comprising platelets (OR-LRWB + PLT), the oxygen and carbon dioxide reduced leukopenia whole blood (OCR-LRWB), the oxygen and carbon dioxide reduced leukopenia whole blood comprising platelets (OCR-LRWB + PLT) has a reduced level of tumor necrosis factor-alpha (TNF-alpha) compared to conventionally stored whole blood. In one aspect, the level of TNF- α in oxygen-reduced leukoreduced whole blood (OR-LRWB), oxygen-reduced leukoreduced whole blood containing platelets (OR-LRWB + PLT), oxygen-and carbon-reduced leukoreduced whole blood (OCR-LRWB), oxygen-and carbon-reduced leukoreduced whole blood containing platelets (OCR-LRWB + PLT) is about half of the level of TNF- α present in conventionally stored blood after 21 days of normalization of hemoglobin concentration. In one aspect, the level of TNF- α in oxygen reduced leukoreduced whole blood (OR-LRWB), oxygen reduced leukoreduced whole blood comprising platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukoreduced whole blood (OCR-LRWB), oxygen and carbon dioxide reduced leukoreduced whole blood comprising platelets (OCR-LRWB + PLT) is about 25% OR less of the level of TNF- α present in conventionally stored blood after 40 days.
In certain aspects, the oxygen reduced leukopenia whole blood (OR-LRWB), the oxygen reduced leukopenia whole blood comprising platelets (OR-LRWB + PLT), the oxygen and carbon dioxide reduced leukopenia whole blood (OCR-LRWB), the oxygen and carbon dioxide reduced leukopenia whole blood comprising platelets (OCR-LRWB + PLT) have reduced Epidermal Growth Factor (EGF) levels compared to conventionally stored whole blood. In one aspect, the level of EGF in oxygen reduced leukopenia whole blood (OR-LRWB), oxygen reduced leukopenia whole blood containing platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukopenia whole blood (OCR-LRWB), oxygen and carbon dioxide reduced leukopenia whole blood containing platelets (OCR-LRWB + PLT) is about half of the level of EGF present in conventionally stored blood after normalization of hemoglobin concentration over 21 days. In one aspect, the level of EGF in the oxygen reduced leukopenia whole blood (OR-LRWB), the oxygen reduced leukopenia whole blood comprising platelets (OR-LRWB + PLT), the oxygen and carbon dioxide reduced leukopenia whole blood (OCR-LRWB), the oxygen and carbon dioxide reduced leukopenia whole blood comprising platelets (OCR-LRWB + PLT) is about 25% OR less of the level of EGF present in conventionally stored blood after 40 days.
In certain aspects, the oxygen reduced leukopenia whole blood (OR-LRWB), the oxygen reduced leukopenia whole blood comprising platelets (OR-LRWB + PLT), the oxygen and carbon dioxide reduced leukopenia whole blood (OCR-LRWB), the oxygen and carbon dioxide reduced leukopenia whole blood comprising platelets (OCR-LRWB + PLT) has a reduced level of soluble CD40 ligands (sCD40L) compared to conventionally stored whole blood. In one aspect, the level of sCD40L in oxygen reduced leukopenia whole blood (OR-LRWB), oxygen reduced leukopenia whole blood including platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukopenia whole blood (OCR-LRWB), oxygen and carbon dioxide reduced leukopenia whole blood including platelets (OCR-LRWB + PLT) is about half of the level of sCD40L present after 21 days of normalization of hemoglobin concentration in conventionally stored blood. In one aspect, the level of sCD40L in oxygen reduced leukopenia whole blood (OR-LRWB), oxygen reduced leukopenia whole blood including platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukopenia whole blood (OCR-LRWB), oxygen and carbon dioxide reduced leukopenia whole blood including platelets (OCR-LRWB + PLT) is about 25% OR less of the level of sCD40L present in conventionally stored blood after 40 days.
In certain aspects, the level of platelet-derived growth factor (PDGF) is reduced in oxygen-reduced leukoreduced whole blood (OR-LRWB), oxygen-reduced leukoreduced whole blood containing platelets (OR-LRWB + PLT), oxygen-and carbon-reduced leukoreduced whole blood (OCR-LRWB), oxygen-and carbon-reduced leukoreduced whole blood containing platelets (OCR-LRWB + PLT) as compared to conventionally stored whole blood. In one aspect, the level of PDGF in the oxygen reduced leukoreduced whole blood (OR-LRWB), the oxygen reduced leukoreduced whole blood containing platelets (OR-LRWB + PLT), the oxygen and carbon dioxide reduced leukoreduced whole blood (OCR-LRWB), the oxygen and carbon dioxide reduced leukoreduced whole blood containing platelets (OCR-LRWB + PLT) is about half the level of PDGF present in conventionally stored blood after 21 days of hemoglobin concentration normalization. In one aspect, the level of PDGF in the oxygen reduced leukoreduced whole blood (OR-LRWB), the oxygen reduced leukoreduced whole blood comprising platelets (OR-LRWB + PLT), the oxygen and carbon dioxide reduced leukoreduced whole blood (OCR-LRWB), the oxygen and carbon dioxide reduced leukoreduced whole blood comprising platelets (OCR-LRWB + PLT) is about 25% OR less of the level of PDGF present in conventionally stored blood after 40 days.
The present disclosure provides and includes oxygen reduced leukoreduced whole blood (OR-LRWB), oxygen reduced leukoreduced whole blood containing platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukoreduced whole blood (OCR-LRWB), oxygen and carbon dioxide reduced leukoreduced whole blood containing platelets (OCR-LRWB + PLT), which when infused into a patient provides a reduced inflammatory response as compared to conventionally stored oxygen reduced leukoreduced whole blood (OR-LRWB), oxygen reduced leukoreduced whole blood containing platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukoreduced whole blood (OCR-wb + PLT), oxygen and carbon dioxide reduced leukoreduced whole blood containing platelets (OCR-LRWB + PLT).
The present disclosure provides and includes oxygen-reduced leukoreduced whole blood (OR-LRWB) that provides a blood product with higher RBC deformability than conventionally stored blood products. In certain aspects, the blood product is a whole blood product. In another aspect, the blood product is leukoreduced whole blood. In another aspect, the blood product is leukoreduced and thrombocytopenic whole blood. In another aspect, the blood product is a leukoreduced packed red blood cell or a white blood cell and a platelet-reduced packed red blood cell.
The present disclosure provides and includes oxygen-reduced leukoreduced whole blood (OR-LRWB) having coagulation parameters that are at least 75% of the coagulation parameters of conventionally stored whole blood as measured by Thromboelastography (TEG). In one aspect, TEG coagulation parameters of oxygen reduced leukoreduced whole blood (OR-LRWB), oxygen reduced leukoreduced whole blood containing platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukoreduced whole blood (OCR-LRWB), oxygen and carbon dioxide reduced leukoreduced whole blood containing platelets (OCR-LRWB + PLT) correspond to conventionally stored blood. In yet another aspect, the oxygen reduced leukoreduced whole blood (OR-LRWB), the oxygen reduced leukoreduced whole blood comprising platelets (OR-LRWB + PLT), the oxygen and carbon dioxide reduced leukoreduced whole blood (OCR-LRWB), the oxygen and carbon dioxide reduced leukoreduced whole blood comprising platelets (OCR-LRWB + PLT) have TEG coagulation parameters greater than TEG coagulation parameters of conventionally stored blood. In one aspect, the TEG angle is greater than 40 °. On the other hand, the TEG kinetics (K) is less than 5 minutes. TEG K, on the other hand, is between 1 and 5 minutes. On the other hand, the TEG maximum amplitude (TEG MA) is greater than 50 mm. On the other hand, the TEG maximum amplitude (TEG MA) is less than 70 mm. On the other hand, the TEG maximum amplitude (TEG MA) is between 30 and 65 mm. On the other hand, the TEG reaction Time (TEGR) is less than 10 minutes. On the other hand, the TEG reaction time (TEG R) is less than 8 minutes. In another aspect, the TEG reaction time (TEG R) is at least 3 minutes. TEG reaction Time (TEGR), on the other hand, is between 4 and 8 minutes.
The present disclosure provides oxygen-reduced leukoreduced whole blood (OR-LRWB) having a coagulation parameter that is at least 75% of the coagulation parameter of conventionally stored whole blood as measured by Prothrombin Time (PT). In one aspect, the PT of oxygen reduced leukoreduced whole blood (OR-LRWB), oxygen reduced leukoreduced whole blood containing platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukoreduced whole blood (OCR-LRWB), oxygen and carbon dioxide reduced leukoreduced whole blood containing platelets (OCR-LRWB + PLT) is equivalent to conventionally stored blood. In yet another aspect, the oxygen reduced leukoreduced whole blood (OR-LRWB), the oxygen reduced leukoreduced whole blood comprising platelets (OR-LRWB + PLT), the oxygen and carbon dioxide reduced leukoreduced whole blood (OCR-LRWB), the oxygen and carbon dioxide reduced leukoreduced whole blood comprising platelets (OCR-LRWB + PLT) have a PT greater than the PT of conventional stored blood. Oxygen-reduced leukopenia whole blood (OR-LRWB), on the other hand, has a PT of less than 15 seconds. Oxygen-reduced leukoreduced whole blood (OR-LRWB), on the other hand, had PT for greater than 5 seconds. Oxygen-reduced leukoreduced whole blood (OR-LRWB) OR PT with 10 to 15 seconds, on the other hand.
The present disclosure provides and includes oxygen reduced leukoreduced whole blood (OR-LRWB), oxygen reduced leukoreduced whole blood containing platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukoreduced whole blood (OCR-LRWB), oxygen and carbon dioxide reduced leukoreduced whole blood containing platelets (OCR-LRWB + PLT), having coagulation parameters that are at least 75% of the coagulation parameters of conventionally stored whole blood (as measured by Partial Thromboplastin Time (PTT)). In one aspect, the PTT of oxygen reduced leukoreduced whole blood (OR-LRWB), oxygen reduced leukoreduced whole blood containing platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukoreduced whole blood (OCR-LRWB), oxygen and carbon dioxide reduced leukoreduced whole blood containing platelets (OCR-LRWB + PLT) is comparable to conventionally stored blood. In yet another aspect, the oxygen reduced leukoreduced whole blood (OR-LRWB), the oxygen reduced leukoreduced whole blood containing platelets (OR-LRWB + PLT), the oxygen and carbon dioxide reduced leukoreduced whole blood (OCR-LRWB), the oxygen and carbon dioxide reduced leukoreduced whole blood containing platelets (OCR-LRWB + PLT) have PTT greater than PTT of conventionally stored blood. In another aspect, the oxygen reduced leukopenia whole blood (OR-LRWB), the oxygen reduced leukopenia whole blood comprising platelets (OR-LRWB + PLT), the oxygen and carbon dioxide reduced leukopenia whole blood (OCR-LRWB), the oxygen and carbon dioxide reduced leukopenia whole blood comprising platelets (OCR-LRWB + PLT) have PTT of greater than 25 seconds. On the other hand, oxygen reduced leukoreduced whole blood (OR-LRWB), oxygen reduced leukoreduced whole blood containing platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukoreduced whole blood (OCR-LRWB), oxygen and carbon dioxide reduced leukoreduced whole blood containing platelets (OCR-LRWB + PLT) have PTT of less than 40 seconds. On the other hand, oxygen reduced leukoreduced whole blood (OR-LRWB), oxygen reduced leukoreduced whole blood containing platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukoreduced whole blood (OCR-LRWB), oxygen and carbon dioxide reduced leukoreduced whole blood containing platelets (OCR-LRWB + PLT) have PTT between 32 and 42 seconds.
The present disclosure provides and includes oxygen reduced leukoreduced whole blood (OR-LRWB), oxygen reduced leukoreduced whole blood containing platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukoreduced whole blood (OCR-LRWB), oxygen and carbon dioxide reduced leukoreduced whole blood containing platelets (OCR-LRWB + PLT), having whole blood (OR-WB) with coagulation parameters at least 75% of coagulation parameters of conventionally stored whole blood, as measured by fibrinogen activity levels. In one aspect, the fibrinogen activity of oxygen reduced leukoreduced whole blood (OR-LRWB), oxygen reduced leukoreduced whole blood containing platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukoreduced whole blood (OCR-LRWB), oxygen and carbon dioxide reduced leukoreduced whole blood containing platelets (OCR-LRWB + PLT) is comparable to conventionally stored blood. In yet another aspect, the oxygen reduced leukopenia whole blood (OR-LRWB), the oxygen reduced leukopenia whole blood comprising platelets (OR-LRWB + PLT), the oxygen and carbon dioxide reduced leukopenia whole blood (OCR-LRWB), the oxygen and carbon dioxide reduced leukopenia whole blood comprising platelets (OCR-LRWB + PLT) have a fibrinogen activity greater than the fibrinogen activity of conventionally stored blood. In another aspect, the oxygen reduced leukopenia whole blood (OR-LRWB), the oxygen reduced leukopenia whole blood comprising platelets (OR-LRWB + PLT), the oxygen and carbon dioxide reduced leukopenia whole blood (OCR-LRWB), the oxygen and carbon dioxide reduced leukopenia whole blood comprising platelets (OCR-LRWB + PLT) have a fibrinogen level of at least 200 mg/ml. On the other hand, oxygen-reduced leukopenia whole blood (OR-LRWB), oxygen-reduced leukopenia whole blood comprising platelets (OR-LRWB + PLT), oxygen-and carbon dioxide-reduced leukopenia whole blood (OCR-LRWB), oxygen-and carbon dioxide-reduced leukopenia whole blood comprising platelets (OCR-LRWB + PLT) have fibrinogen levels of at most 400 mg/ml. On the other hand, oxygen-reduced leukopenia whole blood (OR-LRWB), oxygen-reduced leukopenia whole blood comprising platelets (OR-LRWB + PLT), oxygen-and carbon dioxide-reduced leukopenia whole blood (OCR-LRWB), oxygen-and carbon dioxide-reduced leukopenia whole blood comprising platelets (OCR-LRWB + PLT) have fibrinogen levels of 250 to 350 mg/ml. On the other hand, oxygen-reduced leukopenia whole blood (OR-LRWB), oxygen-reduced leukopenia whole blood comprising platelets (OR-LRWB + PLT), oxygen-and carbon dioxide-reduced leukopenia whole blood (OCR-LRWB), oxygen-and carbon dioxide-reduced leukopenia whole blood comprising platelets (OCR-LRWB + PLT) have fibrinogen levels of 250 to 300 mg/ml.
The present disclosure provides and includes oxygen reduced leukoreduced whole blood (OR-LRWB), oxygen reduced leukoreduced whole blood containing platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukoreduced whole blood (OCR-LRWB), oxygen and carbon dioxide reduced leukoreduced whole blood containing platelets (OCR-LRWB + PLT) having whole blood (OR-WB) with coagulation parameters as measured by D-dimer analysis that are at least 75% of the coagulation parameters of conventionally stored whole blood. In one aspect, the values of D-dimer in oxygen reduced leukoreduced whole blood (OR-LRWB), oxygen reduced leukoreduced whole blood containing platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukoreduced whole blood (OCR-LRWB), oxygen and carbon dioxide reduced leukoreduced whole blood containing platelets (OCR-LRWB + PLT) are comparable to conventionally stored blood. In yet another aspect, the oxygen reduced leukopenia whole blood (OR-LRWB), the oxygen reduced leukopenia whole blood including platelets (OR-LRWB + PLT), the oxygen and carbon dioxide reduced leukopenia whole blood (OCR-LRWB), the oxygen and carbon dioxide reduced leukopenia whole blood including platelets (OCR-LRWB + PLT) have D-dimer values greater than the D-dimer values of conventionally stored blood.
The present disclosure provides and includes oxygen reduced leukoreduced whole blood (OR-LRWB), oxygen reduced leukoreduced whole blood containing platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukoreduced whole blood (OCR-LRWB), oxygen and carbon dioxide reduced leukoreduced whole blood containing platelets (OCR-LRWB + PLT), whole blood having coagulation parameters that are at least 75% of the coagulation parameters of conventionally stored whole blood (OR-WB), as measured by a thrombin generation assay. In one aspect, the thrombin generation values in oxygen reduced leukoreduced whole blood (OR-LRWB), oxygen reduced leukoreduced whole blood containing platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukoreduced whole blood (OCR-LRWB), oxygen and carbon dioxide reduced leukoreduced whole blood containing platelets (OCR-LRWB + PLT) correspond to conventionally stored blood. In yet another aspect, the oxygen reduced leukopenia whole blood (OR-LRWB), the oxygen reduced leukopenia whole blood including platelets (OR-LRWB + PLT), the oxygen and carbon dioxide reduced leukopenia whole blood (OCR-LRWB), the oxygen and carbon dioxide reduced leukopenia whole blood including platelets (OCR-LRWB + PLT) have thrombin generation values greater than thrombin generation values of conventionally stored blood.
The present disclosure provides and includes oxygen reduced leukopenia whole blood (OR-LRWB), oxygen reduced leukopenia whole blood containing platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukopenia whole blood (OCR-LRWB), oxygen and carbon dioxide reduced leukopenia whole blood containing platelets (OCR-LRWB + PLT), with platelet functional parameters that are at least 75% of conventional stored whole blood platelet functional parameters as measured by a platelet aggregometer. In one aspect, platelet function parameters in oxygen reduced leukoreduced whole blood (OR-LRWB), oxygen reduced leukoreduced whole blood containing platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukoreduced whole blood (OCR-LRWB), oxygen and carbon dioxide reduced leukoreduced whole blood containing platelets (OCR-LRWB + PLT) correspond to conventionally stored blood. In yet another aspect, the oxygen reduced leukopenia whole blood (OR-LRWB), the oxygen reduced leukopenia whole blood including platelets (OR-LRWB + PLT), the oxygen and carbon dioxide reduced leukopenia whole blood (OCR-LRWB), the oxygen and carbon dioxide reduced leukopenia whole blood including platelets (OCR-LRWB + PLT) have platelet functional parameters that are greater than platelet functional parameters of conventionally stored blood.
The present disclosure provides and includes oxygen reduced leukopenia whole blood (OR-LRWB), oxygen reduced leukopenia whole blood including platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukopenia whole blood (OCR-LRWB), oxygen and carbon dioxide reduced leukopenia whole blood including platelets (OCR-LRWB + PLT), with coagulation factor levels at least 75% of coagulation factor levels in traditionally stored blood. On the one hand, the level of coagulation factors corresponds to the level of blood that is traditionally stored. In other aspects, the oxygen reduced leukoreduced whole blood (OR-LRWB), the oxygen reduced leukoreduced whole blood comprising platelets (OR-LRWB + PLT), the oxygen and carbon dioxide reduced leukoreduced whole blood (OCR-LRWB), the oxygen and carbon dioxide reduced leukoreduced whole blood comprising platelets (OCR-LRWB + PLT) have platelet function parameters that are greater than platelet function parameters of conventionally stored blood. Without being limited by theory, it is believed that oxidative degradation of coagulation factors may be prevented OR reduced and a higher level of coagulation factor activity may be provided in oxygen reduced leukoreduced whole blood (OR-LRWB), oxygen reduced leukoreduced whole blood containing platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukoreduced whole blood (OCR-LRWB), oxygen and carbon dioxide reduced leukoreduced whole blood containing platelets (OCR-LRWB + PLT). Methods for assessing the effect of treatment on coagulation are known in the art, for example, Pidcoke et al, "Primary static capacity of blood: a comprehensive analysis of pathological reduction and regeneration effects over time, "transfer 53: 137S-149S (2013).
The present disclosure provides and includes oxygen reduced leukoreduced whole blood (OR-LRWB), oxygen reduced leukoreduced whole blood comprising platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukoreduced whole blood (OCR-LRWB), oxygen and carbon dioxide reduced leukoreduced whole blood comprising platelets (OCR-LRWB + PLT), having a level of factor V with a specific activity that is at least 75% of the level of factor V activity present in conventionally stored blood. In one aspect, the specific activity of factor V is comparable to that of conventionally stored blood. In other aspects, the specific activity of factor V is greater than platelet function parameters of conventional storage blood in whole oxygen-reduced leukopenia (OR-LRWB), whole oxygen-reduced leukopenia comprising platelets (OR-LRWB + PLT), whole oxygen-and carbon dioxide-reduced leukopenia (OCR-LRWB), and whole oxygen-and carbon dioxide-reduced leukopenia comprising platelets (OCR-LRWB + PLT). Methods of measuring the specific activity of factor V are known in the art.
The present disclosure provides and includes oxygen reduced leukoreduced whole blood (OR-LRWB), oxygen reduced leukoreduced whole blood comprising platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukoreduced whole blood (OCR-LRWB), oxygen and carbon dioxide reduced leukoreduced whole blood comprising platelets (OCR-LRWB + PLT), having a level of factor V with a specific activity that is at least 75% of the level of factor VIII activity present in conventionally stored blood. In one aspect, the specific activity of factor VIII is comparable to that of conventionally stored blood. In other aspects, the specific activity of factor VIII is greater than the platelet function parameter of conventionally stored blood in whole oxygen-reduced leukopenia (OR-LRWB), whole oxygen-reduced leukopenia comprising platelets (OR-LRWB + PLT), whole oxygen-and carbon dioxide-reduced leukopenia (OCR-LRWB), and whole oxygen-and carbon dioxide-reduced leukopenia comprising platelets (OCR-LRWB + PLT). Methods for measuring specific activity of factor VIII are known in the art. In one aspect, the oxygen reduced leukoreduced whole blood (OR-LRWB), the oxygen reduced leukoreduced whole blood comprising platelets (OR-LRWB + PLT), the oxygen and carbon dioxide reduced leukoreduced whole blood (OCR-LRWB), the oxygen and carbon dioxide reduced leukoreduced whole blood comprising platelets (OCR-LRWB + PLT) have a specific factor V activity of less than 40% after 21 days of storage.
The present disclosure provides and includes oxygen reduced leukopenia whole blood (OR-LRWB), oxygen reduced leukopenia whole blood containing platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukopenia whole blood (OCR-LRWB), oxygen and carbon dioxide reduced leukopenia whole blood containing platelets (OCR-LRWB + PLT), having a level of Antithrombin (AT) having a specific activity that is AT least 75% of the level of AT activity in conventionally stored blood. On the one hand, the specific activity of AT is comparable to that of conventionally stored blood. In other aspects, the specific activity of the AT is greater than platelet function parameters of conventionally stored blood, oxygen-reduced leukopenia whole blood (OR-LRWB + PLT), oxygen-and carbon dioxide-reduced leukopenia whole blood (OCR-LRWB + PLT). Methods for measuring specific activity of AT are known in the art.
The present disclosure provides and includes oxygen reduced leukopenia whole blood (OR-LRWB), oxygen reduced leukopenia whole blood comprising platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukopenia whole blood (OCR-LRWB), oxygen and carbon dioxide reduced leukopenia whole blood comprising platelets (OCR-LRWB + PLT), having a level of factor XIV (autologous thrombin IIA OR protein C) with a specific activity that is at least 75% of the level of factor XIV activity present in conventionally stored blood. In one aspect, the specific activity of factor XIV is comparable to that of conventionally stored blood. In other aspects, oxygen reduced leukoreduced whole blood (OR-LRWB), oxygen reduced leukoreduced whole blood comprising platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukoreduced whole blood (OCR-LRWB), oxygen and carbon dioxide reduced leukoreduced whole blood comprising platelets (OCR-LRWB + PLT), which has a specific activity of factor XIV greater than platelet function parameters of conventionally stored blood. Methods of measuring the specific activity of factor XIV are known in the art.
The present disclosure provides and includes oxygen reduced leukopenia whole blood (OR-LRWB), oxygen reduced leukopenia whole blood including platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukopenia whole blood (OCR-LRWB), oxygen and carbon dioxide reduced leukopenia whole blood including platelets (OCR-LRWB + PLT), having a von willebrand factor (vWF) level with a specific activity that is at least 75% of the vWF activity level in conventionally stored blood. In one aspect, the specific activity of vWF is comparable to that of conventionally stored blood. In other aspects, the oxygen-reduced leukopenia whole blood (OR-LRWB), the oxygen-reduced leukopenia whole blood comprising platelets (OR-LRWB + PLT), the oxygen-and carbon dioxide-reduced leukopenia whole blood (OCR-LRWB), the oxygen-and carbon dioxide-reduced leukopenia whole blood comprising platelets (OCR-LRWB + PLT), has a specific activity of vWF that is greater than platelet function parameters of conventionally stored blood. On the other hand, whole oxygen-reduced leukopenia (OR-LRWB), whole oxygen-reduced leukopenia and platelet containing blood (OR-LRWB + PLT), whole oxygen-and carbon dioxide-reduced leukopenia (OCR-LRWB), whole oxygen-and carbon dioxide-reduced leukopenia and platelet containing blood (OCR-LRWB + PLT), which has a specific activity of vWF that is less than the platelet function parameters of conventionally stored blood. Methods of measuring the specific activity of vWF are known in the art.
The present disclosure provides and includes methods for extending the shelf life of whole blood storage from the current 2 weeks to 3 weeks and beyond. The oxygen reduced leukoreduced whole blood (OR-LRWB), the oxygen reduced leukoreduced whole blood comprising platelets (OR-LRWB + PLT), the oxygen and carbon dioxide reduced leukoreduced whole blood (OCR-LRWB), the oxygen and carbon dioxide reduced leukoreduced whole blood comprising platelets (OCR-LRWB + PLT) of the present disclosure provide patient results for three weeks, which are equivalent to patient results provided by whole blood that has been stored for two weeks under conventional conditions.
As provided herein, oxygen-reduced leukopenia whole blood (OR-LRWB), oxygen-reduced leukopenia whole blood comprising platelets (OR-LRWB + PLT), oxygen-and carbon dioxide-reduced leukopenia whole blood (OCR-LRWB), oxygen-and carbon dioxide-reduced leukopenia whole blood comprising platelets (OCR-LRWB + PLT), reduces side effects of the transfusion recipient compared to conventionally stored blood. In one aspect, oxygen reduced leukopenia whole blood (OR-LRWB), oxygen reduced leukopenia whole blood comprising platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukopenia whole blood (OCR-LRWB), oxygen and carbon dioxide reduced leukopenia whole blood comprising platelets (OCR-LRWB + PLT) have a reduced inflammatory response after two weeks of storage compared to conventionally stored blood. In other aspects, the inflammatory response is a decrease after three weeks relative to the amount of blood traditionally stored. In one aspect, oxygen reduced leukopenia whole blood (OR-LRWB), oxygen reduced leukopenia whole blood comprising platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukopenia whole blood (OCR-LRWB), oxygen and carbon dioxide reduced leukopenia whole blood comprising platelets (OCR-LRWB + PLT) may be stored for more than three weeks and maintain a level of inflammatory response after two weeks compared to conventionally stored blood.
As provided herein, oxygen-reduced leukopenia whole blood (OR-LRWB), oxygen-reduced leukopenia whole blood comprising platelets (OR-LRWB + PLT), oxygen-and carbon dioxide-reduced leukopenia whole blood (OCR-LRWB), oxygen-and carbon dioxide-reduced leukopenia whole blood comprising platelets (OCR-LRWB + PLT), reduces side effects of the transfusion recipient compared to conventionally stored blood. In one aspect, whole blood with oxygen-reduced leukopenia (OR-LRWB), whole blood with oxygen-reduced leukopenia and including platelets (OR-LRWB + PLT), whole blood with oxygen-and carbon-reduced leukopenia (OCR-LRWB), whole blood with oxygen-and carbon-reduced leukopenia and including platelets (OCR-LRWB + PLT) is less immunomodulatory after two weeks of storage than conventionally stored blood. In other aspects, the immunoregulation is reduced after three weeks relative to conventionally stored blood. In one aspect, oxygen reduced leukopenia whole blood (OR-LRWB), oxygen reduced leukopenia whole blood comprising platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukopenia whole blood (OCR-LRWB), oxygen and carbon dioxide reduced leukopenia whole blood comprising platelets (OCR-LRWB + PLT) may be stored for more than three weeks and maintain a level of immune regulation compared to conventionally stored blood after two weeks.
The methods and whole blood products of the invention provide improved patient outcomes upon transfusion. In particular, oxygen reduced leukoreduced whole blood (OR-LRWB), oxygen reduced leukoreduced whole blood comprising platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukoreduced whole blood (OCR-LRWB), oxygen and carbon dioxide reduced leukoreduced whole blood comprising platelets (OCR-LRWB + PLT) provide improved survival of cancer patients provided in perioperative transfusions. In a certain aspect, oxygen reduced leukopenia whole blood (OR-LRWB), oxygen reduced leukopenia whole blood including platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukopenia whole blood (OCR-LRWB), oxygen and carbon dioxide reduced leukopenia whole blood including platelets (OCR-LRWB + PLT) provide perioperative reduced mortality and improved survival for pancreatic cancer patients. Without being limited by theory, the reduced mortality is a result of reduced cytokine levels and improved oxygen transport and delivery due to increased levels of 2, 3-DPG and ATP.
In one aspect, blood for infusion into a cancer patient in need thereof has reduced levels of activation-regulated cytokines, normal T cell expression and secretion (RANTES). In one aspect, the RANTES level corresponds to the RANTES level at the beginning of storage. On the other hand, the level of RANTES in oxygen reduced leukoreduced whole blood (OR-LRWB), oxygen reduced leukoreduced whole blood containing platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukoreduced whole blood (OCR-LRWB), oxygen and carbon dioxide reduced leukoreduced whole blood containing platelets (OCR-LRWB + PLT) is lower than that in conventionally stored blood. In one aspect, the level of RANTES is lower than the level of RANTES in blood traditionally stored during storage. In other aspects, RANTES does not increase during storage.
On the one hand, blood transfused to a cancer patient in need thereof has a reduced level of CC chemokine as eotaxin, and on the other hand, the reduced level of eotaxin in oxygen-reduced leukopenia whole blood (OR-LRWB), oxygen-reduced leukopenia whole blood containing platelets (OR-LRWB + PLT), oxygen-and carbon dioxide-reduced leukopenia whole blood (OCR-LRWB), oxygen-and carbon dioxide-reduced leukopenia whole blood containing platelets (OCR-LRWB + PLT) is eotaxin-1, also referred to as C-C motif chemokine 11. In one aspect, the level of eotaxin corresponds to the level of eotaxin present at the beginning of storage. On the other hand, whole blood with oxygen-reduced leukopenia (OR-LRWB), whole blood with oxygen-reduced leukopenia and including platelets (OR-LRWB + PLT), whole blood with oxygen-and carbon-reduced leukopenia (OCR-LRWB), whole blood with oxygen-and carbon-reduced leukopenia and including platelets (OCR-LRWB + PLT) had a lower level of eotaxins than that present in conventionally stored blood. In one aspect, the level of eotaxin is lower than the level of eotaxin present in blood during conventional storage periods. In other aspects, eotaxin does not increase during storage.
The methods and whole blood products of the invention provide reduced risk of multiple organ failure syndrome and improved patient outcomes upon transfusion. In particular, oxygen reduced leukopenic whole blood (OR-LRWB), oxygen reduced leukopenic whole blood comprising platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukopenic whole blood (OCR-LRWB), oxygen and carbon dioxide reduced leukopenic whole blood comprising platelets (OCR-LRWB + PLT) provide a reduced acute lung multiple organ failure risk syndrome in perioperative transfusions. In a certain aspect, oxygen reduced leukoreduced whole blood (OR-LRWB), oxygen reduced leukoreduced whole blood comprising platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukoreduced whole blood (OCR-LRWB), oxygen and carbon dioxide reduced leukoreduced whole blood comprising platelets (OCR-LRWB + PLT) provide a reduced multiple organ failure risk syndrome in trauma patients during emergency treatment.
The present disclosure provides and includes a method of preparing oxygen reduced leukopenia whole blood comprising obtaining a whole blood unit comprising an anticoagulant, filtering the whole blood to produce leukoreduced whole blood, consuming the leukoreduced whole blood of oxygen, and storing the oxygen reduced leukoreduced whole blood under anaerobic conditions.
The present disclosure provides and includes a method of preparing oxygen reduced leukopenia whole blood having 30% or less (SO)2) And pre-storing oxygen saturation. Whole blood obtained from donors using venipuncture has a range of from about 30% to about 70% Saturated Oxygen (SO)2) Oxygen saturation of (a). In certain aspects, SO2To 25% or less. In certain aspects, SO2To 20% or less. In certain aspects, the sulfur dioxide is reduced to 15% or less. In other aspects, SO2To 10% or less. In other aspects, SO2To 5% or less.
Also provided and included in the present disclosure are compositions and methods of preparing oxygen reduced and carbon dioxide reduced leukopenia whole blood compositions. In certain aspects, SO2The value is 20% or less and the partial pressure of carbon dioxide is less than 60 mmHg. In other aspects, the partial pressure of carbon dioxide is between 10 and 60 mmHg. On the other hand, the partial pressure of carbon dioxide is between 20 and 40 mmHg. Also included are whole blood compositions and methods that provide an SO of 15% or less2And a carbon dioxide partial pressure of 10-60 mmHg. In another aspect, the methods and compositions include compositions having an SO of 15% or less2And a carbon dioxide partial pressure of 20-40 mmHg. In another aspect, the blood compositions and methods of the present disclosure have an SO of 10% or less 2And a carbon dioxide partial pressure of 10-60 mmHg. In other aspects, the blood compositions and methods of the present disclosure have an SO of 10% or less2And a carbon dioxide partial pressure of 20-40 mmHg. In yet another aspect, the blood compositions and methods of the present disclosure have an SO of 5% or less2And a carbon dioxide partial pressure between 10 and 60 mmHg. In other aspects, the blood compositions and methods of the present disclosure have an SO of 5% or less2And a carbon dioxide partial pressure between 20 and 40 mmHg.
Also provided and included in the present disclosure are compositions and methods for preparing oxygen reduced and carbon dioxide reduced leukoreduced whole blood.In certain aspects, SO2The value is 20% or less and the partial pressure of carbon dioxide is between 1 and 60 mmHg. In other aspects, the partial pressure of carbon dioxide is between 10 and 60 mmHg. In another aspect, the partial pressure of carbon dioxide is 20 to 40mmHg or 1 to 20 mmHg. Also included are whole blood compositions and methods that provide an SO of 15% or less2And a carbon dioxide partial pressure of 10-60 mmHg. In certain aspects, SO2The value is 15% or less and the partial pressure of carbon dioxide is between 1 and 60 mmHg. In another aspect, the methods and compositions include compositions having an SO of 15% or less2And a carbon dioxide partial pressure of 20 to 40mmHg or 1 to 20 mmHg. In another aspect, the blood compositions and methods of the present disclosure have an SO of 10% or less 2And a carbon dioxide partial pressure of 1 to 60mmHg or 10 to 60 mmHg. In other aspects, the blood compositions and methods of the present disclosure have an SO of 10% or less2And a carbon dioxide partial pressure of 20 to 40mmHg or 1 to 20 mmHg. In other aspects, the blood compositions and methods of the present disclosure have an SO of 5% or less2And a carbon dioxide partial pressure of 1 to 60mmHg or 10 to 60 mmHg. In other aspects, the blood compositions and methods of the present disclosure have an SO of 5% or less2And a carbon dioxide partial pressure of 20 to 40mmHg or 1 to 20 mmHg.
Notably, as shown in FIGS. 2A, 2B, 3A and 3B, the ATP levels in the blood reduced by stored oxygen are dependent on CO2Partial pressure of (c). Specifically, oxygen is consumed to about 10% SO2And reducing carbon dioxide to about 25mmHg resulted in an increase in 2, 3-DPG levels for more than 21 days, while ATP was reduced to about half of the initial value. See fig. 2G and 3D. Thus, the present disclosure provides and includes SO that oxygen is consumed to about 5%2Levels and partial pressures that consume carbon dioxide to about 30 to 40mmHg to produce 2, 3-DPG with increased levels of oxygen and carbon dioxide reduced whole blood, and at least 50% of the initial concentration of ATP is maintained on day 20. In other aspects, the CO can be adjusted 2To maintain the ATP level at least 75% of the initial ATP value. In view of this disclosure, one of ordinary skill in the art can experimentally determine CO2And (4) adjusting the level.
Long term cryogenic storage under conventional conditions is known to compromise the deformability of the stored RBCs, possibly compromising their ability to perfuse the microvascular network and deliver oxygen to tissues and vital organs upon infusion. Oxidative damage is thought to be a major cause of loss of biomechanical function of erythrocytes; thus, storage of red blood cells under reduced Oxygen (OR) and reduced oxygen and carbon dioxide (OCR) conditions improves oxidative damage and thus maintains the primary rheological properties better than conventional (aerobic) storage. For this study, we have used an in vitro microfluidic system to re-embody an in vivo microvascular capillary bed to demonstrate a reduction in the effect of oxygen on stored cells.
The present disclosure provides and includes methods of managing blood banks that improve the availability of blood products to trauma victims and patients in need of multiple transfusions and provide for preservation of overall blood resources. The blood component preparation can be prepared from whole blood as stored herein for transfusion or incorporated into a bulk transfusion kit. In addition to improved blood chemistry (low hemolysis, improved 2, 3-DPG, etc.), the method also provides improved hemostasis and improved deformability.
In aspects according to the present description, the methods provide for maintaining an inventory of blood units comprising oxygen-reduced whole blood and anticoagulant as described above, providing one OR more blood units in the inventory for treating a patient, and recovering the blood units from the inventory to prepare a separated oxygen-reduced blood component comprising oxygen-reduced plasma and oxygen-reduced leukopenia packed red blood cells (OR-LRpRBC + PLT) comprising platelets. In some aspects, the anticoagulant comprises citrate-phosphate-dextrose (CPD), citrate-phosphate-dextrose with adenine (CPDA-1), or CP 2D.
In one aspect, the present specification provides a method for maintaining an inventory of blood units comprising oxygen and carbon dioxide reduced leukopenia whole blood and an anticoagulant as described above, providing one or more blood units from the inventory to treat a patient, and recovering the blood units from the inventory to prepare a component of packaged red blood cells (OCR-LRpRBC + PLT) that separates the oxygen and carbon dioxide reduced blood and the oxygen and carbon dioxide reduced leukopenia and contain platelets. In some aspects, the anticoagulant comprises citrate-phosphate-dextrose (CPD), citrate-phosphate-dextrose with adenine (CPDA-1), or anticoagulant citrate phosphate diglucose (CP 2D).
The specification further provides for preparing one OR more bulk transfusion kits comprising oxygen-reduced plasma, oxygen-reduced leukopenia packaged red blood cells comprising platelets (OR-LRpRBC + PLT), oxygen-and carbon dioxide-reduced plasma, and oxygen-and carbon dioxide-reduced leukopenia packaged red blood cells comprising platelets (OCR-LRpRBC + PLT).
In aspects according to the invention, unused blood in the inventory is recirculated after a period of time. In certain aspects where the anticoagulant is CPD, the blood units are recirculated before three weeks of storage. In other aspects where the anticoagulant is CPDA-1, the blood units are recirculated before five weeks of storage. In other aspects, the blood units are recirculated after 2 weeks or less. In one aspect, the blood unit recovery occurs between 2 days and 1 week. Recovery, on the other hand, occurs between 2 days and 2 weeks. In certain aspects, the recovering occurs between 1 week and 2 weeks. The time of recovery may vary depending on the turnover and needs of the blood facility.
Although the recycling process is preferably carried out under anaerobic conditions, the process may also be carried out under aerobic conditions. Aerobic conditions may save costs, but may also be displayed in higher turnover facilities. In high turnover facilities, the recovered blood components may be used shortly after the recirculation process, and further storage of the blood under anaerobic conditions may provide little additional benefit.
The method for managing blood banks further provides for the preparation of a number of blood transfusion kits as described in detail below.
The present disclosure provides and includes: a blood product supply method for transfusion medicine is provided, comprising consuming oxygen from leukoreduced whole blood to prepare oxygen-reduced leukoreduced whole blood (OR-LRWB + PLT), storing the oxygen-reduced leukoreduced whole blood (OR-LRWB + PLT) for a period of time, and providing the stored blood to a patient in need thereof. In certain aspects, the leukopenia step comprises platelet reduction to produce oxygen-reduced leukopenia whole blood (OR-LRWB).
The present disclosure provides and includes: a method for transfusing a pharmaceutical blood product is provided comprising depleting oxygen and carbon dioxide from leukoreduced whole blood to prepare oxygen and carbon dioxide reduced leukoreduced whole blood (OCR-LRWB + PLT), storing the oxygen and carbon dioxide reduced leukoreduced whole blood (OCR-LRWB + PLT) for a period of time, and providing the stored blood to a patient in need thereof. In certain aspects, the leukopenia step includes platelet reduction to produce oxygen and carbon dioxide reduced leukopenia whole blood (OCR-LRWB).
The present disclosure provides and includes: a blood product supply method for transfusion medicine is provided, including consuming oxygen from leukopenia whole blood to prepare oxygen-reduced leukopenia whole blood (OR-LRWB + PLT), storing the oxygen-reduced leukopenia whole blood (OR-LRWB + PLT) for a period of time, preparing packed red blood cells (OR-LRpRBC + PLT) that are oxygen-reduced leukopenia and contain platelets. In certain aspects, the leukocyte reduction step comprises platelet reduction to produce oxygen-reduced leukopenia packaged red blood cells (OR-LRpRBC).
The present disclosure provides and includes: a method for transfusing a pharmaceutical blood product is provided, comprising depleting oxygen and carbon dioxide from leukoreduced whole blood to produce oxygen and carbon dioxide reduced leukoreduced whole blood (OCR-LRWB + PLT), storing the oxygen and carbon dioxide reduced leukoreduced whole blood (OCR-LRWB + PLT) for a period of time, and producing packed red blood cells (OCR-LRpRBC + PLT) which are oxygen and carbon dioxide reduced leukoreduced and contain platelets. In certain aspects, the leukopenia step includes platelet reduction to produce oxygen and carbon dioxide reduced leukopenia packaged red blood cells (OCR-LRpRBC).
As provided herein, OR-LRpRBC + PLT, OR-LRpRBC, OCR-LRpRBC + PLT and OCR-LRpRBC may be returned to a supply store of blood products for supply and storage for a period of time until needed by the patient. In aspects of the present disclosure, the total storage time of the RBC product as a whole blood product or as a package can be up to six weeks. In some aspects, the second storage period is between 2 and 4 weeks.
Methods of providing a blood product supply include and provide for consumption of oxygen or oxygen and carbon dioxide. The oxygen levels that provide a means for supplying blood products are discussed in detail above. In certain aspects, SO2The value is reduced to 20% or less and the partial pressure of carbon dioxide is less than 60 mmHg. In other aspects, the partial pressure of carbon dioxide is between 10 and 60 mmHg. On the other hand, the partial pressure of carbon dioxide is between 20 and 40 mmHg. Further comprising providing 15% or less SO2And a carbon dioxide partial pressure of 10 to 60 mmHg. In another aspect, the method provides a composition having an SO of 15% or less2And a carbon dioxide partial pressure of 20-40 mmHg. In another aspect, the methods of the present disclosure provide a composition having an SO of 10% or less2And a carbon dioxide partial pressure of 10-60 mmHg. In other aspects, the method for providing a blood product supply provides an SO of 10% or less 2And a carbon dioxide partial pressure of 20-40 mmHg. In a further aspect, the process provides an SO of 5% or less2And a carbon dioxide partial pressure of 10-60 mmHg. In other aspects, the method provides an SO of 5% or less2And a carbon dioxide partial pressure of 20-40 mmHg.
The present disclosure provides and includes novel blood components obtained during blood component recovery of OR-LRWB + PLT and OCR-LRWB + PLT. As described above, while conventional whole blood products have FDA-approved shelf lives (3 weeks for WB in CPD and 5 weeks for CPDA 1), clinicians using WB limit their shelf lives to between 2 and 14 days. In routine storage, blood is often discarded. In the present disclosure, OR-LRWB + PLT and OCR-LRWB + PLT can be processed using conventional component separation methods modified to maintain blood in an OR OR OCR depleted state. Generally, the method is modified to incorporate oxygen and carbon dioxide impermeable barriers to the assembly and features to prevent oxygen ingress. Suitable methods can be found, for example, in International patent application No. PCT/US2016/021794 filed on 10/3/2016 and International patent application No. PCT/US2016/029069 filed on 22/4/2016, both of which are incorporated herein by reference.
In accordance with aspects of the present disclosure, a blood composition is provided comprising oxygen-reduced packed red blood cells and having a red blood cell density of less than 1 x 105Platelet of leukocyte of L. Such compositions are available from OR-LRWB + PLT and OCR-LRWB + PLT. In one aspect, the level of leukocytes is less than 1X 104and/L of leucocytes. In aspects according to the disclosure, the oxygen saturation of packed red blood cells (OR-LRpRBC + PLT) that are leukopenia and contain platelets is less than 30%. In one aspect, oxygen reduces leukopenia and oxygen saturation of packed red blood cells comprising platelets (OR-LRpRBC + PLT) is less than 20%. In one aspect, oxygen reduces leukopenia and oxygen saturation of packed red blood cells comprising platelets (OR-LRpRBC + PLT) is less than 10%. On the other hand, oxygen reduces leukopenia and the oxygen saturation of packed red blood cells comprising platelets (OR-LRpRBC + PLT) is less than 5%.
The present disclosure provides and includes packaged red blood cells (OCR-LRpRBC + PLT) that are leukopenic to oxygen and carbon dioxide and that contain less than 30% sulfur dioxide and platelets with a partial carbon dioxide storage pressure of less than 60 mmHg. In one aspect, the OCR-LRpRBC + PLT has an oxygen saturation of less than 30% and a carbon dioxide reserve partial pressure of 20-40 mmHg. In one aspect, the OCR-LRpRBC + PLT has an oxygen saturation of less than 30% and a carbon dioxide storage partial pressure of between 0 and 20 mmHg. In one aspect, the OCR-LRpRBC + PLT has an oxygen saturation of less than 20% and a partial carbon dioxide storage pressure of less than 60 mmHg. In one aspect, the OCR-LRpRBC + PLT has an oxygen saturation of less than 20% and a partial carbon dioxide storage pressure of 20-40 mmHg. In one aspect, OCR-LRpRBC + PLT has an oxygen saturation of less than 20% and a carbon dioxide partial storage pressure of between 0-20 mmHg. OCR-LRpRBC + PLT, on the other hand, has an oxygen saturation of less than 15% and a partial carbon dioxide storage pressure of less than 60 mmHg. In one aspect, the OCR-LRpRBC + PLT has an oxygen saturation of less than 15% and a partial carbon dioxide storage pressure of 20-40 mmHg. In one aspect, OCR-LRpRBC + PLT has an oxygen saturation of less than 15% and a partial storage pressure of carbon dioxide between 0-20 mmHg. OCR-LRpRBC + PLT, on the other hand, has an oxygen saturation of less than 10% and a partial carbon dioxide storage pressure of less than 60 mmHg. In one aspect, the OCR-LRpRBC + PLT has an oxygen saturation of less than 10% and a partial carbon dioxide storage pressure of 20-40 mmHg. In one aspect, OCR-LRpRBC + PLT has an oxygen saturation of less than 10% and a carbon dioxide partial storage pressure of between 0-20 mmHg. In another aspect, the OCR-LRpRBC + PLT has an oxygen saturation of less than 5% and a partial carbon dioxide storage pressure of less than 60 mmHg. In one aspect, the OCR-LRpRBC + PLT has an oxygen saturation of less than 5% and a partial storage pressure of carbon dioxide between 20-40 mmHg. In one aspect, OCR-LRpRBC + PLT has an oxygen saturation of less than 5% and a carbon dioxide partial storage pressure of between 0-20 mmHg.
Packed red blood cells that are leukopenic in oxygen and contain platelets (OR-LRpRBC + PLT) and whole blood that is leukopenic in oxygen and carbon dioxide and contains platelets (OCR-LRWB + PLT) typically also contain an additive solution. Suitable additive solutions according to the present disclosure include AS-1, AS-3 (R) ((R))
) AS-5, SAGM, PAGG-SM, PAGG-GM, MAP, AS-7, ESOL-5, EAS61, OFAS1, OFAS3, and combinations thereof. In one aspect, the additive solution is added during separation of the components. In one aspect, the additive solution is AS-1. In another aspect, the additive solution is AS-3. In other aspects, the additive solution is SAGM.
The methods and compositions of the present disclosure provide and include the preparation of "mass transfusion kits" (MTKs) with improved properties of kits prepared from conventional components. The bulk transfusion kits of the present disclosure can be prepared in various configurations according to clinical needs. The MTK of the present disclosure is stored under anaerobic or anaerobic and carbon dioxide free conditions until ready for use. OR and OCR conditions may be maintained by sealing in an impermeable housing, with OR without a suitable adsorbent material. The MTK of the present disclosure may be re-oxidized prior to use, or used directly. In general, the specifications specify that optimized bulk transfusion kits can provide red blood cells with improved levels of 2, 3-DPG. Such kits are prepared from component blood products of whole blood (OCR-LRWB + PLT) with reduced leukopenia with oxygen and carbon dioxide and containing platelets. Alternatively, kits can be prepared using component blood products obtained from whole blood (OR-LRWB + PLT) with oxygen-reduced leukopenia and containing platelets to generate kits with higher levels of ATP. Kits prepared using the methods of the present specification provide platelets suitable for hemostasis along with oxygen-reduced stored red blood cells. Thus, the bulk transfusion kit of the present description can increase platelet availability without additional dilution, while further providing higher quality (e.g., more deformable, more 2, 3-DPG, less storage lesion) RBCs. Importantly, the recovery of blood components from the oxygen-reduced whole blood of the present disclosure increases the availability of transfusion products for trauma victims, saving and conserving valuable and limited resources. As described above, conventional bulk transfusion kits comprise a volume of plasma, a volume of pRBC, and a volume of platelets in a 1: 1 ratio, wherein the amounts of the three components correspond to a unit of "reconstituted blood" for serial or parallel infusion into a patient in need thereof. The regenerated blood does not directly correspond to whole blood, does not contain additive solution and has higher anticoagulant content. The further reconstituted blood typically comprises a larger volume than the typical unit of whole blood. The reconstituted blood of the present disclosure is improved over conventional reconstituted blood in that it provides additional platelets in the pRBC portion (e.g., oxygen and carbon dioxide reduced leukopenia packaged red blood cells containing platelets (OCR-LRpRBC + PLT) and oxygen reduced leukopenia packaged red blood cells containing platelets (OR-LRpRBC + PLT). such cryopreserved platelets are often referred to as Platelet Storage Lesions (PSLs), and cold stored platelets are rapidly excreted from the circulation in vivo.
The present disclosure provides and includes a bulk transfusion kit comprising a volume of oxygen reduced leukopenia and platelet containing packaged red blood cells (OR-LRpRBC + PLT), oxygen and carbon dioxide reduced leukopenia and platelet containing whole blood (OCR-LRWB + PLT), OR a combination thereof. In one aspect, a bulk transfusion kit provides a volume of plasma and a volume of LRpRBC + PLT. In one aspect, the volume of plasma and the volume of LRpRBC + PLT is 1: 1. In other aspects, the ratio of plasma to LRpRBC + PLT is between 1: 1 and 1: 2 by volume. In one aspect, the volume ratio of plasma to LRpRBC + PLT is about 1: 2.
The present disclosure provides and includes, a bulk transfusion kit comprising additional platelets with plasma and packed red blood cells with oxygen reduced leukopenia and containing platelets (OR-LRpRBC + PLT) OR whole blood with oxygen and carbon dioxide reduced leukopenia and containing platelets (OCR-LRWB + PLT).
The bulk transfusion kit of the present disclosure provides a volume of plasma. The plasma of MTK may be fresh plasma or thawed Fresh Frozen Plasma (FFP). The specification provides for obtaining plasma of MTK from conventional sources (e.g., non-oxygen reduced) or oxygen reduced or oxygen and carbon dioxide reduced sources.
In one aspect, the plasma of the MTK of the present disclosure may be obtained from oxygen reduced leukopenia whole blood (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukopenia whole blood (OCR-LRWB + PLT). Without being limited by theory, plasma obtained from an oxygen-reduced source will have lower levels of storage lesions, including, for example, lower levels of cytokines, isoprostane, and microparticles. As provided herein, MTK with plasma, platelets, and pRBC according to the present description is provided in a 1: 1 or 1: 2 ratio by volume. It will be understood by those of ordinary skill in the art that the MTKs of the present disclosure, like conventional MTKs, are designed to provide the equivalent of a blood unit. It should be appreciated that any arbitrary total volume may be selected while keeping the necessary ratios mentioned equal to the reconstituted blood.
Examples
Example 1: cytokine, cell-free hemoglobin and isoprostane accumulation during anaerobic storage of packed red blood cells
15 pRBC units were collected from normal healthy donors according to Yoshida et al, "Aerobic Storage of Red Blood Cells In a Novel Additive Solution In vivo Recovery," transfer 49: 458-64(2008), storing each unit separately as follows: one under standard blood bank conditions (control) and the other anaerobic conditions (test). At weeks 0, 1, 2, 3 and 6, samples were taken using sterile connection equipment from the PRBC unit. Plasma samples were frozen for the following assays: 8-isoprostane F by Mass Spectroscopy Using Procarta ImmunoImmunoAnalyzing magnetic bead kit2αAnd a single batch test of 22 cytokines by cell-free hemoglobin in a HemoCue plasma/photometer (HemoCue AB, Angelholm, sweden).
As shown in FIG. 1A, at week 2, eotaxin reached a statistically significant difference at week 2 (86.6 pg/ml-control (C), 64.9-test (t), p-value-0.00213, p < 0.05 with statistical significance; day 42 (292-C, 112-t; p ═ 0.000) as shown in FIG. 1B, RANTES was different at all time points, starting at day 3 (374.6-C, 55.1-t), p ═ 0.00000; very large difference was observed at day 42 (3371.6-C, 88.4-t; p < 0.002) as shown in FIG. 1C, no-cell hemoglobin difference was observed at week 2 (96.0mg/D1-C, 41.7-t), p ═ 0.00001; day 42 (170-C, 63-t, p ═ 0.0001. D), the difference in isoprostaglandin was shown on day 3 of storage (45.5pg/ml-c, 32.1-t), p-0.00689; day 42 (101.9-c, 64.7-t, p ═ 0.0048).
Example 2: whole blood collection, whitening and gas consumption
Blood units from donor patients are collected into anticoagulant solutions comprising CPDA1 or CPDA according to standard protocols, including collection of heparin barrels. The collected blood containing anticoagulant was leukopenic within 4 hours after the initial blood draw according to the manufacturer's instructions. Baseline ABL90 blood gas and metabolic parameters were determined from donor heparin tubes and whole blood products according to standard procedures. Please refer to BSL Handbook Procedure BSL-P024: procedure Manual and Radiometer ABL90FLEX Gas Analyzer instruments.
Anaerobic controls were prepared from each leukopenia blood by transferring 120mL LRWB/CPDA-1 or LRWB/CPD into 150mL transfer bags, labeled as needed and placed at room temperature (15-30 ℃).
The remaining portion of LRWB/CPDA-1 or LRWB/CPD was treated for consumption of oxygen or oxygen and carbon dioxide by transfer to a blood treatment bag connected to Sorin D100 and treated for 5 minutes at a flow rate of 700 ml/min without gas generating BOF treatment control. 120g of the resulting BOF processed blood was transferred to a 300ml transfer bag that had been stored under anaerobic conditions and labeled BOF treatment control. The remaining LRWB/CPDA-1 or LRWB/CPD was treated on Sorin D100 at a peak flow rate of 700 ml/min with a gas flow of 3 l/min and a gas composition of 5% CO 2And 95% N2Until the blood reaches 5% SO2Blood gas values were measured on a Radiometer ABL90FLEX gas analyzer at intervals of 3 to 5 minutes. To reduce the carbon dioxide content, the gas mixture was switched to 100% N2For 1-4 minutes until SO2Up to 5. + -. 1%, and pCO2The deoxygenation rate was monitored by monitoring the blood gas values every 15-30 seconds to reach 30 + -3 mmHg. 120g of the resulting oxygen and carbon dioxide reduced LRWB/CPDA-1 or LRWB/CPD was transferred to a 300ml transfer bag previously stored under anaerobic conditions as described above and labeled ("C"). On Sorin D100 with 99% N2And 1% of O2Further treatment of LRWB/CPDA-1 or LRWB/CPD was carried out at a flow rate of 700ml/min until LRWB/CPDA-1 or LRWB/CPD reached 5. + -. 1% SO2、pCO2Reaching 7 +/-3 mmHg. 120g of the resulting oxygen and carbon dioxide reduced LRWB/CPDA-1 or LRWB/CPD were transferred to a 300ml transfer bag previously stored under anaerobic conditions as described above and labeled ("D"). Additional samples were processed as described above using the new Sorin D100. Immediately following preparation of each sample, the ABL90 blood gas level was determined according to the manufacturer's instructions to establish a baseline SO2And pCO2Horizontal (e.g., T0). See BSL Handbook Procedures. Samples for cytokine analysis were collected and stored at-80 ℃ for later analysis.
All samples were analyzed as provided in example 6 below.
Example 3: storage of anaerobic test products
The oxygen-reduced and oxygen and carbon dioxide-reduced blood transfer bags are wrapped in a mesh, secured with elastic, and placed in an anaerobic jar with a 4-sorbent bag (Mitsubishi, SS-300). The canister was sealed and purged of air using an Alicat gas handling system. See BSL Handbook Procedure BSL-P040: a Procedure for preparing Blood Products in Aerobic Storage in canister. The anaerobic and aerobic blood is placed in a refrigerator at 1 to 6 c. The tank gauge was monitored daily to ensure a reading of 5 + -1 psi. Tanks below 2psi were adjusted to standard procedures. See BSL Handbook Procedure BSL-P040: procedure for planning Blood Products in Anaerobic Storage in canister.
Example 4: example testing
Samples were tested at the indicated time points: day 0 (T)0) Post-treatment, day 1, week 2 and week 3. For a given test, the sample may be tested fresh or frozen. Tests included Complete Blood Count (CBC), Thromboelastography (TEG).
Platelet Rich Plasma (PRP) was immediately prepared for platelet aggregation as per the manufacturer's instructions.
Coagulation screening and additional testing were performed according to the manufacturer's instructions.
Cytokine samples were prepared immediately according to the manufacturer's instructions.
Example 5: ATP sampling and measurement
Samples were measured by deproteinizing and precipitating ATP. 1ml of sample (e.g. LRWB/CPD or LRWB/CPDA-1 or above) was precipitated with 1.0ml ice-cold trichloroacetic acid (TCA) (12% w/v) and vortexed for 15 to 30 seconds and incubated on ice for 5 min. The tubes containing the TCA/sample mixture were centrifuged at 3600g for 5 min at 4 ℃. Samples were immediately processed to minimize TCA exposure. The clear supernatant was transferred to a pre-cooled tube and snap frozen on a dry ice alcohol bath and stored at-70 ℃.
Example 6: improved deformability in RBCs stored under reduced oxygen conditions
Agreed from health by standard 500mL blood donationsNine (9) individual units of whole blood were obtained from volunteers. Processing the whole blood donation into leukocyte-reduced red blood cell (LR-RBC) units according to standard AABB/FDA guidelines; the resulting cell was then divided in half. As described in examples 2 and 3, half of the units are O2And CO2And (4) reducing.
The obtained sample is placed in anaerobic low-temperature storage, and the rear half part is placed in conventional aerobic low-temperature storage. Paired red blood cell units were stored in a blood bank refrigerator and evaluated weekly for the entire 6 week storage period. Prior to testing, the hematocrit of all RBC samples was adjusted to 40% using saline (0.9% NaCl; RBC-S). The deformability of RBC-S at the beginning of and during the study was determined as described in international patent publication No. wo2013/177339, published on 28/11/2013. A high-speed image sequence (-150 FPS) of a blood sample across an artificial microvascular network (AMVN) chip was recorded. The occlusion time, the amount of time that the non-deformable cells are occluding through the network, and the frequency of blood engulfment through the network (occlusion frequency) are determined.
For oxygen and carbon dioxide controlled blood, the overall mass perfusion rate through the AMVN system is consistently higher compared to the units of aerobic storage, while the total occlusion time of the oxygen reduced red blood cells is consistently lower (table 1). These results indicate that the reduction of oxygen content in LR-RBC units reduces the deterioration of the biomechanical properties of red blood cells during cryogenic storage.
Hypoxia and storage processes significantly reduce the rate at which the rheological properties of RBCs deteriorate during cryogenic storage, and enable the maintenance of more physiologically relevant biomechanical properties of red blood cells during storage. In combination with the benefits of whole blood infusion, improved deformability of red blood cells suggests that preserved red blood cell function will improve retention of red blood cells after transfusion and increase the ability of the infused red blood cells to diffuse into the microvasculature.
Table 1: perfusion rate of blood cells after oxygen-reduced storage
Example 7: deoxygenation of platelets does not interfere with hemostatic properties
Eight (8) units of Whole Blood (WB) were obtained from healthy consenting volunteers by standard 500mL blood donations. Donated whole Blood was collected in a CPDA-1 anticoagulant and filtered with a platelet retention filter (C.sub.C.) as described in example 2(Research Blood Components, Inc.) 
WB-SP) (LRWB; terumo Medical Corporation). The resulting filtration unit was then divided in half. Half of the units are placed in conventional, aerobic cryogenic storage, while the next half year is further divided, anaerobic, cryogenic storage. The anaerobic storage device is oxygen reduced (OR-LRWB) OR oxygen and carbon dioxide reduced (OCR-LRWB). Treating anaerobically stored units with Sorin D100 membrane oxygenator to produce oxygenated water having about 5% SO2And about 35mm Hgp CO2The anaerobic unit of (1). The resulting anaerobic unit was placed in a standard PVC bag and stored in an anaerobic tank containing oxygen adsorbent and nitrogen. Paired leukopenic platelet units were stored every 21 days as described below.
The units evaluated according to the manufacturer's instructions included metabolic parameters of percent hemolysis (low plasma, Angelholm sweden), ATP (DiaSys, Flacht, germany) and 2, 3-DPG (Sigma-Aldrich, st. louis, M0). As shown in FIG. 4A, the reduced ATP levels in the stored OCR-LRWBs remained unchanged, but the ATP levels in the stored OR-LRWBs increased, compared to the conventionally stored LRWBs (solid lines). As shown in FIG. 4B, the stored OCR-LRWB and OR-LRWB maintained the level of 2, 3-DPG for up to 21 days compared to the conventional stored LRWB. Furthermore, as shown in FIG. 4C, there was no significant change in blood stability when comparing the stored OR-LRWB and the stored OCR-LRWB with the conventionally stored LRWB (solid line).
Plasma coagulation parameters of traditionally stored LRWB and OCR-LRWB were evaluated by assessing Prothrombin Time (PT), activated partial prothrombin time (aPTT) and levels of fibrinogen and D-dimer. As shown in FIG. 5, the aPPT and PT are somewhat but not significantly elongated in the conventional stored LRWB (solid line). Furthermore, no evidence of coagulation activation was observed as evidence of similar fibrinogen and D-dimer levels.
Plasma coagulation factors of traditionally stored LRWB and OCR-LRWB were further evaluated by determining the levels of factor V, VIII, protein C activity, protein S activity and von willebrand factor (vWF) activity. Protein C and protein S analysis ACL was used separately according to manufacturer' S instructions
(Instrument laboratory) and
(diagnostic Stago, Inc.). As shown in FIG. 6, the levels of factor V, factor VIII, protein C activity, protein S activity and vWF were not significantly changed in anaerobic, cryogenically stored OCR-LRWB (dotted line) compared to traditionally stored WB (solid line).
Traditionally stored LRWB and OCR-LRWB Haemoscope was used according to manufacturer's instructions
The analyzer (Haemonetics) and Thromboelastography (TEG) further assessed the coagulation function. As shown in FIGS. 7A to 7D, no significant difference was observed in propagation (TEG angle), amplification (TEGK), maximum amplitude (TEGMA) or reaction time (TEG R) in OCR-LRWB (dotted line) compared to the conventionally stored LRWB (solid line).
While the disclosure has been described with reference to a specific embodiment, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the disclosure. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the disclosure without departing from the scope thereof.
Therefore, it is intended that the disclosure not be limited to the particular embodiment disclosed as the best mode contemplated for carrying out this disclosure, but that the disclosure will include all embodiments falling within the scope and spirit of the appended claims.
The present application also relates to the following embodiments:
1. a method for improving survival of a patient in need of multiple transfusions comprising providing oxygen reduced stored red blood cells (OR-stored RBCs) to a patient in need of a medical procedure.
2. The method of embodiment 1, wherein said OR-stored RBCs are oxygen and carbon dioxide reduced (OCR-stored RBCs).
3. The method of embodiment 1 OR 2, wherein said OR-stored RBCs comprise a reduced level of the factor RANTES unbound as compared to conventionally stored red blood cells (stored RBCs).
4. The method of any one of embodiments 1 to 3, wherein the level of RANTES is less than 500pg/ml after 21 days.
5. The method of any one of embodiments 1 to 4, wherein the level of RANTES is less than 300pg/ml after 21 days of storage under deoxygenated conditions.
6. The method of any one of embodiments 1 to 5, wherein said OR-stored RBCs comprise reduced levels of eotaxin compared to conventionally stored red blood cells (stored RBCs).
7. The method of any one of embodiments 1 to 6, wherein said level of eotaxin is less than 150pg/ml after 21 days of storage under deoxygenated conditions.
8. The method of any one of embodiments 1 to 7, wherein said level of eotaxin is less than 100pg/ml after 21 days of storage under deoxygenated conditions.
9. The method of any one of embodiments 1 to 8, wherein said OR-stored RBCs are selected from the group consisting of: oxygen-reduced leukopenia whole blood (OR-LRWB), oxygen-reduced leukopenia whole blood comprising platelets (OR-LRWB + PLT), oxygen-reduced leukopenia packaged red blood cells (OR-LRpRBC), oxygen-reduced leukopenia packaged red blood cells comprising platelets (OR-LRpRBC + PLT), oxygen-and carbon dioxide-reduced leukopenia whole blood (OCR-LRWB), oxygen-and carbon dioxide-reduced leukopenia whole blood comprising platelets (OCR-LRWB + PLT), oxygen-and carbon dioxide-reduced leukopenia packaged red blood cells (OCR-LRpRBC), oxygen-and carbon dioxide-reduced leukopenia packaged red blood cells comprising platelets (OCR-LRpRBC + PLT), and combinations thereof.
10. The method of any one of embodiments 1 to 9, wherein said OR-stored RBCs comprise oxygen reduced leukoreduced whole blood (OR-LRWB), oxygen reduced leukoreduced whole blood containing platelets (OR-LRWB + PLT), oxygen and carbon dioxide reduced leukoreduced whole blood (OCR-LRWB), oxygen and carbon dioxide reduced leukoreduced whole blood containing platelets (OCR-LRWB + PLT).
11. The method of any one of embodiments 1 to 10, wherein the patient in need of multiple transfusions is a trauma patient, a transplant patient, a cardiac surgery patient, an obstetric patient, a GI surgery patient, or an orthopedic surgery patient.
12. The method of any one of embodiments 1 to 11, wherein the trauma patient is a bleeding trauma patient or a blunt trauma patient.
13. The method of any one of embodiments 1 to 12, wherein the patient is a cancer patient and the OR-stored RBCs are oxygen-reduced leukopenia packaged red blood cells (OR-LRpRBC), oxygen-reduced leukopenia packaged red blood cells (OR-LRpRBC + PLT) comprising platelets, oxygen-and carbon dioxide-reduced leukopenia packaged red blood cells (OCR-LRpRBC), OR oxygen-and carbon dioxide-reduced leukopenia packaged red blood cells (OCR-LRpRBC + PLT) comprising platelets.
14. A method for improving survival of a cancer patient in need of perioperative blood transfusion comprising providing oxygen-reduced stored red blood cells (OR-stored RBCs) to a patient in need of a medical procedure.
15. The method of embodiment 14, wherein said OR-stored RBCs are oxygen and carbon dioxide reduced red blood cells (OCR-stored RBCs).
16. The method of embodiment 14 OR 15, wherein the OR-stored RBCs are oxygen-reduced leukoreduced packaged red blood cells (OR-LRpRBC), oxygen-reduced leukoreduced packaged red blood cells comprising platelets (OR-LRpRBC + PLT), oxygen-and carbon dioxide-reduced leukoreduced packaged red blood cells (OCR-LRpRBC), OR oxygen-and carbon dioxide-reduced leukoreduced packaged red blood cells comprising platelets (OCR-LRpRBC + PLT).
17. The method of any one of embodiments 14 to 16, wherein said OR-stored RBCs comprise reduced levels of the factor RANTES OR eotaxin as compared to non-oxygen reduced stored red blood cells (stored RBCs).
18. The method of any one of embodiments 14 to 17, wherein said level of RANTES is less than 500pg/ml after 21 days, or said level of eotaxin is less than 150pg/ml after 21 days of storage under deoxygenated conditions.
19. A method for reducing cytokines in stored blood, comprising:
collecting blood into an anticoagulant solution;
(ii) reducing leukocytes from the collected blood;
saturation of pre-Stored Oxygen (SO)2) Reduced to 30% or less; and
storing the collected oxygen-reduced blood under anaerobic conditions to produce oxygen-reduced stored blood.
20. The method of embodiment 19, further comprising removing plasma and adding additional solution to prepare packaged red blood cells (OR-pRBC + PLT) that are oxygen reduced and contain platelets.
21. The method of embodiment 19, wherein said reduction of said leukocytes further comprises reducing platelets.
22. The method of embodiment 21, further comprising removing plasma and adding additional solution to prepare oxygen-reduced packaged red blood cells (OR-pRBC).
23. The method of any one of embodiments 19 to 22, wherein the level of one or more cytokines is reduced compared to non-oxygen reduced stored blood cells (stored RBCs).
24. The method of any one of embodiments 19 to 23, wherein the cytokine is selected from the group consisting of: monocyte chemoattractant protein-1 (MCP-1), chemokine (RANTES) that regulates expression and secretion of activated normal T cells, angiogenin, tumor necrosis factor-alpha (TNF-alpha), Epidermal Growth Factor (EGF), soluble CD40 ligand (sCD40L), and Platelet Derived Growth Factor (PDGF).
25. The method of embodiment 19, wherein reducing the pre-stored oxygen saturation further comprises reducing the pre-stored carbon dioxide partial pressure to less than 60 mmHg.
26. The method of embodiment 25, further comprising removing plasma and adding additional solution to prepare packaged red blood cells depleted of oxygen and carbon dioxide and comprising platelets (OCR-pRBC + PLT).
27. The method of embodiment 25, wherein said reduction of said white blood cells further comprises reducing platelets.
28. The method of embodiment 27, further comprising removing plasma and adding additional solution to prepare oxygen reduced packaged red blood cells (OR-pRBC).
29. The method of any one of embodiments 19 or 25 to 28, wherein the oxygen-reduced stored blood comprises a reduced level of the factor RANTES as compared to non-oxygen-reduced stored red blood cells (stored red blood cells).
30. The method of any one of embodiments 19 or 25 to 29, wherein said oxygen-reduced stored blood comprises a reduced level of eotaxin as compared to non-oxygen-reduced stored red blood cells (stored red blood cells).
31. The method of embodiment 19, wherein said oxygen-reduced stored blood has an elevated level of 2, 3-DPG, wherein said oxygen-reduced leukopenia blood has a level of 2, 3-DPG that is higher than the initial level of 2, 3-DPG in leukoreduced blood over 15 days.
32. The method of embodiment 19 or 31, wherein the level of 2, 3-DPG is at least 80% or more greater than the level of 2, 3-DPG in blood on day 0.
33. The method of any one of embodiments 19, 31 to 32, wherein said level of 2, 3-DPG is between 5 and 20 μmol 2, 3-DPG/gHb on day 21.
34. The method of any one of embodiments 19 to 33, wherein said oxygen-reduced stored blood is selected from the group consisting of: oxygen-reduced leukopenia whole blood (OR-LRWB), oxygen-reduced leukopenia whole blood comprising platelets (OR-LRWB + PLT), oxygen-reduced leukopenia packaged red blood cells (OR-LRpRBC), oxygen-reduced leukopenia packaged red blood cells comprising platelets (OR-LRpRBC + PLT), oxygen-and carbon dioxide-reduced leukopenia whole blood (OCR-LRWB), oxygen-and carbon dioxide-reduced leukopenia whole blood comprising platelets (OCR-LRWB + PLT), oxygen-and carbon dioxide-reduced leukopenia packaged red blood cells (OCR-LRpRBC), oxygen-and carbon dioxide-reduced leukopenia packaged red blood cells comprising platelets (OCR-LRpRBC + PLT), and combinations thereof.
35. A blood composition for infusion into a patient in need of trauma comprising a composition having a pre-stored and stored oxygen Saturation (SO) of 30% or less 2) Oxygen-reduced leukopenia whole blood (OR-LRWB) in an anticoagulant solution, having a 2, 3-DPG level higher than the initial 2, 3-DPG level in the oxygen-reduced leukopenia whole blood over 15 days, OR comprising a blood sample having a pre-storage and storage oxygen Saturation (SO) of 30% OR less2) And pre-stored and stored carbon dioxide partial pressure of less than 60mmHg of oxygen and carbon dioxide reduced leukopenia whole blood (OCR-LRWB), wherein the OCR-LRWB has an Adenosine Triphosphate (ATP) level of at least 3 μmol/gHb.
36. The blood composition of embodiment 35, wherein said 2, 3-DPG level of OR-LRWB is at least 80% OR higher than 2, 3-DPG level of blood at day 0.
37. The blood composition of embodiment 35 OR 36, wherein said 2, 3-DPG level of said OR-LRWB is at least 5 to 20DPG μmol/gHb.
38. The blood composition of any one of embodiments 35-37, wherein the pre-stored oxygen saturation is less than 20%, less than 10%, or less than 5%.
39. The blood composition of any one of embodiments 35 to 38, wherein the pre-storage partial pressure is between 1 and 60mmHg, 10 and 60mmHg, 20 and 40mmHg, 1 and 20 mmHg.
40. The blood composition of any one of embodiments 35 to 39, wherein said anticoagulant solution is adenine-containing citrate-phosphate-dextrose (CPDA1) or citrate-phosphate-dextrose (CPD).
41. The blood composition of any one of embodiments 35 to 40, wherein said oxygen reduced leukopenia whole blood (OR-LRWB) OR oxygen and carbon dioxide reduced leukopenia whole blood (OCR-LRWB) has a reduced level of a Biological Response Modifier (BRM) selected from the group consisting of: cytokines, chemokines, isoprostanes, and oxidized lipid products.
42. The blood composition of embodiment 41, wherein the patient into whom the oxygen reduced leukopenia whole blood (OR-LRWB) OR the oxygen and carbon dioxide reduced leukopenia whole blood (OCR-LRWB) is infused has a reduced inflammatory response.
43. The blood composition of embodiment 41 OR 42, wherein the patient who has been infused with the oxygen reduced leukopenia whole blood (OR-LRWB) OR the oxygen and carbon dioxide reduced leukopenia whole blood (OCR-LRWB) has reduced immunomodulation.
44. The blood composition of any one of embodiments 41 to 43, wherein the patient who has been infused with the oxygen reduced leukopenia whole blood (OR-LRWB) OR the oxygen and carbon dioxide reduced leukopenia whole blood (OCR-LRWB) has a reduced risk of multiple organ failure.
45. The blood composition of any one of embodiments 41-44, wherein the patient into whom the oxygen reduced leukopenia whole blood (OR-LRWB) OR the oxygen and carbon dioxide reduced leukopenia whole blood (OCR-LRWB) is infused has a reduced risk of sepsis.
46. The blood composition of any one of embodiments 41 to 45, wherein the patient into whom the oxygen reduced leukopenia whole blood (OR-LRWB) OR the oxygen and carbon dioxide reduced leukopenia whole blood (OCR-LRWB) is input has a reduced risk of infection.
47. The blood composition of any one of embodiments 41 to 46, wherein the patient into whom the oxygen reduced leukopenia whole blood (OR-LRWB) OR the oxygen and carbon dioxide reduced leukopenia whole blood (OCR-LRWB) is input has a reduced risk of death.
48. The blood composition of any one of embodiments 41 to 47, wherein a patient into whom said oxygen reduced leukopenia whole blood (OR-LRWB) OR oxygen and carbon dioxide reduced leukopenia whole blood (OCR-LRWB) is infused has a higher Red Blood Cell (RBC) deformation.
49. The blood composition of any one of embodiments 41-48, wherein said blood has equivalent OR better coagulation parameters as compared to non-oxygen reduced leukopenia whole blood (OR-LRWB) OR non-oxygen and carbon dioxide reduced leukopenia whole blood (OCR-LRWB), the coagulation parameters determined by Thromboelastography (TEG).
50. The blood composition of any one of embodiments 41-49, wherein said blood has equivalent OR better coagulation parameters as compared to non-oxygen reduced leukopenia whole blood (OR-LRWB) OR non-oxygen and carbon dioxide reduced leukopenia whole blood (OCR-LRWB), the coagulation parameters determined by PT/PTT.
51. The blood composition of any one of embodiments 41 through 50, wherein the blood has equivalent OR better coagulation parameters as determined by a platelet aggregation meter compared to non-oxygen reduced leukopenia whole blood (OR-LRWB) OR non-oxygen and carbon dioxide reduced leukopenia whole blood (OCR-LRWB).
52. The blood composition of any one of embodiments 41-51, wherein the blood has equivalent OR better levels of coagulation factors including factor V, factor VIII, AT, Protein C, OR vWF as compared to non-oxygen reduced leukopenia whole blood (OR-LRWB) OR non-oxygen and carbon dioxide reduced leukopenia whole blood (OCR-LRWB).
53. The blood composition of any one of embodiments 41-52, wherein the blood is safe for transfusion into a patient in need thereof for at least 3 weeks.
54. A method of reducing inflammatory response in a patient receiving a blood transfusion, comprising infusing into a patient in need thereof an oxygen-reduced blood product, wherein the oxygen-reduced blood product has a reduced level of inflammatory factors after storage under anaerobic conditions.
55. The method of embodiment 54, wherein said reduced level of an inflammatory factor is reduced levels of eotaxin or RANTES as compared to non-oxygen reduced stored red blood cells.
56. The method of embodiment 54 or 55, wherein the blood product is selected from the group consisting of: oxygen-reduced leukopenia whole blood (OR-LRWB), oxygen-reduced leukopenia whole blood comprising platelets (OR-LRWB + PLT), oxygen-reduced leukopenia packaged red blood cells (OR-LRpRBC), oxygen-reduced leukopenia packaged red blood cells comprising platelets (OR-LRpRBC + PLT), oxygen-and carbon dioxide-reduced leukopenia whole blood (OCR-LRWB), oxygen-and carbon dioxide-reduced leukopenia whole blood comprising platelets (OCR-LRWB + PLT), oxygen-and carbon dioxide-reduced leukopenia packaged red blood cells (OCR-LRpRBC), oxygen-and carbon dioxide-reduced leukopenia packaged red blood cells comprising platelets (OCR-LRpRBC + PLT), plasma, and combinations thereof.
57. A method of reducing immune modulation in a patient receiving a blood transfusion comprising infusing an oxygen-reduced blood product into a patient in need thereof, wherein said oxygen-reduced blood product has a reduced level of a cytokine after storage under anaerobic conditions, wherein said level of said cytokine is compared to a non-oxygen reduced blood product.
58. The method of embodiment 57, wherein the cytokine is selected from the group consisting of: monocyte chemoattractant protein-1 (MCP-1), chemokine (RANTES) that regulates expression and secretion of activated normal T cells, angiogenin, tumor necrosis factor-alpha (TNF-alpha), Epidermal Growth Factor (EGF), soluble CD40 ligand (sCD40L), and platelet-derived growth factor (PDGF).
59. The method of embodiment 57 or 58, wherein said cytokine is eotaxin or RANTES.
60. The method of any one of embodiments 57 to 59, wherein the blood product is selected from the group consisting of: oxygen-reduced leukopenia whole blood (OR-LRWB), oxygen-reduced leukopenia whole blood comprising platelets (OR-LRWB + PLT), oxygen-reduced leukopenia packaged red blood cells (OR-LRpRBC), oxygen-reduced leukopenia packaged red blood cells comprising platelets (OR-LRpRBC + PLT), oxygen-and carbon dioxide-reduced leukopenia whole blood (OCR-LRWB), oxygen-and carbon dioxide-reduced leukopenia whole blood comprising platelets (OCR-LRWB + PLT), oxygen-and carbon dioxide-reduced leukopenia packaged red blood cells (OCR-LRpRBC), oxygen-and carbon dioxide-reduced leukopenia packaged red blood cells comprising platelets (OCR-LRBC + PLT), plasma, platelet concentrates, and combinations thereof.
61. A method for improving oxygen perfusion in a patient in need thereof, comprising infusing an oxygen-reduced blood product into the patient in need thereof, wherein the oxygen-reduced blood product has higher RBC deformability than conventionally stored blood products.
62. The method of embodiment 61, wherein said oxygen-reduced blood product is selected from the group consisting of: oxygen-reduced leukopenia whole blood (OR-LRWB), oxygen-reduced leukopenia whole blood comprising platelets (OR-LRWB + PLT), oxygen-reduced leukopenia packaged red blood cells (OR-LRpRBC), oxygen-reduced leukopenia packaged red blood cells comprising platelets (OR-LRpRBC + PLT), oxygen-and carbon dioxide-reduced leukopenia whole blood (OCR-LRWB), oxygen-and carbon dioxide-reduced leukopenia whole blood comprising platelets (OCR-LRWB + PLT), oxygen-and carbon dioxide-reduced leukopenia packaged red blood cells (OCR-LRpRBC), oxygen-and carbon dioxide-reduced leukopenia packaged red blood cells comprising platelets (OCR-lrbc + PLT), plasma, platelet concentrates, and combinations thereof.
63. The method of embodiment 61 OR 62, wherein the oxygen-reduced blood product is a recovered blood product comprising oxygen-reduced leukopenia packaged red blood cells (OR-LRpRBC), oxygen-reduced leukopenia packaged red blood cells (OR-LRpRBC + PLT) comprising platelets, oxygen-and carbon dioxide-reduced leukopenia packaged red blood cells (OCR-LRpRBC), OR oxygen-and carbon dioxide-reduced (OCR-LRpRBC + PLT), by component separation from oxygen-reduced leukopenia whole blood (OR-LRWB), oxygen-and carbon dioxide-reduced leukopenia whole blood (OCR-WB + PLT), oxygen-and carbon dioxide-reduced leukopenia whole blood (OCR-WB + LRPLT) comprising platelets after storage for at least one week, Plasma removal and addition of additional solution.
64. The method of any one of embodiments 61 to 63, wherein said salvaged blood product is stored for up to 42 days, 56 days, or 64 days.
65. A method of managing a blood bank, comprising:
maintaining an inventory of blood units comprising oxygen-reduced whole blood and anticoagulant, or oxygen-reduced leukopenia whole blood and anticoagulant;
providing one or more of the blood units from the inventory for treating a patient;
recovering blood units from the inventory to produce component-separated oxygen-reduced blood units.
66. The method of embodiment 65, wherein the component isolated oxygen reduced blood units comprise packed red blood cells that are oxygen reduced leukopenia and comprise platelets (OR-LRpRBC + PLT), packed red blood cells that are oxygen and carbon dioxide reduced leukopenia and comprise platelets (OCR-LRpRBC + PLT), oxygen reduced plasma, OR a combination thereof.
67. The method of embodiment 65 or 66, wherein said component separated oxygen reduced blood units are recovered to prepare a bulk transfusion kit.
68. The method of any one of embodiments 65 to 67, wherein said anticoagulant comprises citrate-phosphate-glucose (CPD) or adenine-containing citrate-phosphate-dextrose (CPDA-1).
69. The method of any one of embodiments 65 to 68, wherein for blood units comprising CPD, said salvage blood units are performed 3 weeks prior to storage and for blood units comprising CPDA1, said salvage blood units are performed 5 weeks prior to storage.
70. The method of any one of embodiments 65 to 69, wherein said salvage blood units are performed at 2 weeks.
71. The method of any of embodiments 65 to 70, wherein said salvage blood units are performed under anaerobic conditions.
72. The method of any one of embodiments 65 to 71, wherein said component-separated oxygen-reduced blood units are stored for up to 6 weeks after addition of additional solution.
73. The method of any of embodiments 65 to 72, further comprising preparing a bulk transfusion kit comprising a volume of plasma and packed red blood cells that are leukoreduced and contain platelets (LRpRBC + PLT).
74. The method of embodiment 73, wherein the ratio of said plasma to said LRpRBC + PLT is 1: 1 by volume.
75. The method of embodiment 73 or 74, wherein the ratio of the plasma to the LRpRBC + PLT is 1: 2 by volume.
76. The method of embodiment 73, wherein said bulk transfusion kit further comprises a volume of platelets, wherein the ratio of said plasma, said platelets to said LRpRBC + PLT is a volume ratio of 1: 1.
77. The method of embodiment 73 or 76, wherein said bulk transfusion kit further comprises a volume of platelets, wherein the ratio of said plasma, said platelets to said LRpRBC + PLT is 1: 2 by volume.
78. A method of providing a supply of blood product for transfusion of a drug, comprising:
consuming oxygen or carbon dioxide from whole blood to produce oxygen reduced whole blood (or oxygen and carbon dioxide reduced whole blood); and
storing the oxygen or oxygen and carbon dioxide reduced whole blood for a period of time and providing the stored blood to a patient in need thereof; or
Storing the oxygen or oxygen and carbon dioxide reduced whole blood for a period of time and preparing oxygen or oxygen and carbon dioxide reduced packed red blood cells.
79. The method of embodiment 78, wherein the oxygen and carbon dioxide reduced packed red blood cells are stored for a second period of time and then provided to a patient in need thereof.
80. The method of embodiment 78 or 79, wherein the second period of time is up to 6 weeks.
81. A blood composition comprising packed oxygen-reduced red blood cells and platelets containing less than 1 x 105L leukocytes.
82. The blood composition of embodiment 81, wherein the composition comprises less than 1 x 104L leukocytes.
83. The blood composition of embodiment 81 or 82, further comprising an additional solution selected from the group consisting of: AS-1, AS-3: (
) AS-5, SAGM, PAGG-SM, PAGG-GM, MAP, AS-7, ESOL-5, EAS61, OFAS1, OFAS3, and combinations thereof.
84. A bulk transfusion kit comprising a volume of plasma and a volume of LRpRBC + PLT.
85. The bulk transfusion kit of embodiment 84, wherein the ratio of the plasma to the LRpRBC + PLT is a 1: 1 volume ratio.
86. The bulk transfusion kit of embodiment 84 or 85, wherein the ratio of said plasma to said LRpRBC + PLT is a volume ratio of 1: 2.
87. The bulk transfusion kit of embodiment 84, further comprising a volume of platelets, wherein the ratio of said plasma, said platelets, and said LRpRBC + PLT is 1: 1 by volume.
88. The bulk transfusion kit of embodiment 84 or 87, further comprising a volume of platelets, wherein the ratio of said plasma, said platelets, and said LRpRBC + PLT is a 1: 1 ratio by volume.
Claims (27)
1. A method for reducing cytokines in stored whole blood, comprising:
Collecting whole blood into an anticoagulant solution;
depleting leukocytes from the collected whole blood to produce leukoreduced whole blood comprising platelets (LRWB + PLT);
saturation of pre-Stored Oxygen (SO)2) LRWB + PLT (OR-LRWB + PLT) reduced to 30% OR less to produce oxygen reduction; and
storing the OR-LRWB + PLT under anaerobic conditions to prepare stored whole blood that is oxygen-reduced leukopenia and comprises platelets, wherein the level of cytokines in the stored OR-LRWB + PLT is reduced compared to conventionally stored non-oxygen-reduced leukopenia and platelet comprising whole blood (non-OR-LRWB + PLT).
2. The method of claim 1, further comprising removing plasma and adding additional solution to the stored OR-LRWB + PLT to prepare stored packed red blood cells (OR-LRpRBC + PLT) that are oxygen-reduced in leukopenia and contain platelets.
3. The method of claim 1, wherein the reduction of the white blood cells further comprises reducing platelets.
4. The method of claim 3, further comprising removing plasma and platelets from the stored OR-LRWB + PLT and adding additional solution to the stored OR-LRWB + PLT to make oxygen reduced leukopenia stored packed red blood cells (OR-LRpRBC).
5. The method of claim 1, wherein the cytokine is selected from the group consisting of: monocyte chemoattractant protein-1 (MCP-1), chemokines that regulate expression and secretion of activated normal T cells (RANTES), angiogenin, tumor necrosis factor-alpha (TNF-alpha), Epidermal Growth Factor (EGF), soluble CD40 ligand (sCD40L), Platelet Derived Growth Factor (PDGF), and any combination thereof.
6. The method of claim 1, wherein said reducing said pre-stored oxygen saturation further comprises pre-stored carbon dioxide partial pressure (pCO)2) To less than 60 millimeters of mercury (mmHg).
7. The method of claim 6, further comprising removing plasma from the stored OR-LRWB + PLT and adding additional solution to the stored OR-LRWB + PLT to prepare stored packaged red blood cells (OCR-LRpRBC + PLT) that are leukoreduced in oxygen and carbon dioxide and contain platelets.
8. The method of claim 6, wherein the reduction of the white blood cells further comprises reducing platelets.
9. The method of claim 8, further comprising removing plasma from the stored OR-LRWB + PLT and adding additional solution to the stored OR-LRWB + PLT to make oxygen and carbon dioxide reduced leukopenia packaged red blood cells (OCR-LRpRBC).
10. The method of claim 1 OR claim 6, wherein the stored OR-LRWB + PLT comprises a reduced level of unbound factors (RANTES) that modulate the expression and secretion of activated normal T cells compared to the conventionally stored non-OR-LRWB + PLT.
11. The method of claim 1 OR claim 6, wherein the stored OR-LRWB + PLT comprises a reduced level of eotaxin compared to the conventionally stored non-OR-LRWB + PLT.
12. The method of claim 1, wherein the stored OR-LRWB + PLT has a 2, 3-diphosphoglycerate (2, 3-DPG) level after 15 days of storage that is higher than the initial 2, 3-DPG level of the OR-LRWB + PLT at day 0.
13. The method of claim 12, wherein the 2, 3-DPG level of the stored OR-LRWB + PLT is at least 80% higher than the initial 2, 3-DPG level of the stored OR-LRWB + PLT at day 0 after 15 days of storage.
14. The method of claim 12, wherein the 2, 3-DPG level of the stored OR-LRWB + PLT is between 5 and 20 micromoles (μmol) of 2, 3-DPG per gram of hemoglobin (gHb) after 21 days of storage.
15. The method of any one of claims 1 to 14, wherein the stored whole blood reduced in oxygen and comprising platelets is selected from the group consisting of: stored whole blood with oxygen-reduced leukocytes and comprising platelets (OR-LRWB + PLT), stored packed red blood cells with oxygen-reduced leukocytes and comprising platelets (OR-LRpRBC + PLT), stored whole blood with oxygen-and carbon-dioxide-reduced leukocytes and comprising platelets (OCR-LRWB + PLT), stored packed red blood cells with oxygen-and carbon-dioxide-reduced leukocytes and comprising platelets (OCR-LRpRBC + PLT), and any combination thereof.
16. The method of claim 1 OR claim 5, wherein the level of the cytokine in the stored OR-LRWB + PLT is reduced by at least 50% after 21 days of storage compared to the conventionally stored non-OR-LRWB + PLT.
17. The method of claim 1 OR claim 5, wherein the level of the cytokine in the stored OR-LRWB + PLT is relatively unchanged after 10 days of storage under anaerobic conditions.
18. The method of claim 17, wherein the level of the cytokine in the stored OR-LRWB + PLT is relatively unchanged after 30 days of storage under anaerobic conditions.
19. The method of claim 18, wherein the level of the cytokine in the stored OR-LRWB + PLT is relatively unchanged after 40 days of storage under anaerobic conditions.
20. The method of any one of claims 2, 4, 7 and 9, wherein the additive solution is selected from the group consisting of: additive solution 1(AS-1), additive solution 3(AS-3), additive solution 5(AS-5), saline-adenine-glucose-mannitol (SAGM), phosphoric acid-adenine-glucose-guanosine-saline-mannitol (PAGG-SM), phosphoric acid-adenine-glucose-guanosine-gluconate-mannitol (PAGG-GM), mannitol-adenine-phosphoric acid (MAP), additive solution 7(AS-7), erythrosol-5(ESOL-5), experimental additive solution 61(EAS61), oxygen free additive solution 1(OFAS1), oxygen free additive solution 3(OFAS3), and any combination thereof.
21. The method of claim 20, wherein the additive solution is AS-1.
22. The method of claim 20, wherein the additive solution is AS-3.
23. The method of claim 20, wherein the additive solution is SAGM.
24. The method of claim 10, wherein the unbound level of the RANTES factor in the stored OR-LRWB + PLT is reduced by at least 50% after 21 days of storage compared to the conventionally stored non-OR-LRWB + PLT.
25. The method of claim 10, wherein the unbound level of the RANTES factor in the stored OR-LRWB + PLT is reduced by at least 25% after 40 days of storage compared to the conventionally stored non-OR-LRWB + PLT.
26. The method of claim 11, wherein said level of said eotaxin in said stored OR-LRWB + PLT is reduced by at least 50% after 21 days of storage as compared to said conventionally stored non-OR-LRWB + PLT.
27. The method of claim 11, wherein said level of said eotaxin in said stored OR-LRWB + PLT is reduced by at least 25% after 40 days of storage as compared to said conventionally stored non-OR-LRWB + PLT.
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